Controlled release granulations of water-soluble active pharmaceutical ingredients

ABSTRACT

Pharmaceutical granulations having a functional coating surrounding a core containing a water-soluble active pharmaceutical ingredient are disclosed. The functional coating provides for immediate release or controlled release of the active pharmaceutical ingredient. The pharmaceutical granulations can be used in oral pharmaceutical compositions.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 63/059,514 filed on Jul. 31, 2020; and U.S.Provisional Application No. 63/040,780 filed on Jun. 18, 2020, each ofwhich is incorporated by reference in its entirety.

FIELD

The disclosure relates to pharmaceutical granulations of water solubleactive pharmaceutical ingredients having functional coating. The coatedpharmaceutical granulations can be used in controlled release oralformulations.

BACKGROUND

In certain methods of treatment, it is necessary to administer a highdose of an active pharmaceutical ingredient. To minimize the amount ofan oral pharmaceutical composition administered to a patient in suchtreatments, it is desirable that the pharmaceutical composition containsa high content of the active pharmaceutical ingredient and that theamount of pharmaceutical excipients be minimized.

Oral controlled-release dosage forms can contain granules coated with afunctional coating that provides a desired release profile in thegastrointestinal tract.

Controlled release formulations containing pharmaceutical granulationshaving a high bulk density of an active pharmaceutical ingredient,suitable for dosing from once or two times a day are desired. To improvepalatability, it is desirable that the pharmaceutical granulations havea low average particle size such as less than 500 μm.

SUMMARY

According to the present invention, pharmaceutical granulations comprisea plurality of coated granules, wherein, the coated granules comprise acore and a functional coating surrounding the core; the core comprisesnot less than 90 wt % of an active pharmaceutical ingredient, wherein,the active pharmaceutical ingredient has an aqueous solubility greaterthan 100 mg/mL; and wt % is based on the total weight of the core; andthe functional coating comprises a plasticizer.

According to the present invention, pharmaceutical compositions comprisea pharmaceutical granulation according to the present invention.

According to the present invention, methods of providing atherapeutically effective amount of γ-hydroxybutyric acid in thesystemic circulation of a patent for treating a disease compriseadministering to a patient in need of such treatment a therapeuticallyeffective amount of a pharmaceutical composition according to thepresent invention, for treating the disease.

According to the present invention, methods of treating a disease in apatient, wherein the disease is known to be treated by administeringγ-hydroxybutyric acid, comprise administering to a patient in need ofsuch treatment a therapeutically effective amount of a pharmaceuticalcomposition according to the present invention, for treating thedisease.

According to the present invention, methods of coating a pharmaceuticalgranulation comprise applying a coating composition to a pharmaceuticalgranulation comprising a plurality of granules, wherein the coatingcomposition comprises: from 4 wt % to 12 wt % solids; greater than 10 wt% water; and from 75 wt % to 92 wt % ethanol; wherein wt % is based onthe total weight of the coating composition; and the granules comprise:a core comprising no less than 90 wt % of an active pharmaceuticalingredient; and the active pharmaceutical ingredient has an aqueoussolubility greater than 100 mg/mL, wherein wt % is based on the totalweight of the core.

BRIEF DESCRIPTION OF THE DRAWINGS

Those skilled in the art will understand that the drawings describedherein are for illustration purposes only. The drawings are not intendedto limit the scope of the present disclosure.

FIG. 1 shows dissolution profiles of an active pharmaceutical ingredientfrom granules having a coating of a methacrylic acid-methyl acrylatecopolymer as described in Example 1.

FIG. 2 shows dissolution profiles of an active pharmaceutical ingredientfrom granules having a coating of ethylcellulose and hydroxypropylcellulose as described in Example 2.

FIG. 3 shows dissolution profiles of an active pharmaceutical ingredientfrom granules having a coating of a methacrylic acid-methyl acrylatecopolymer as described in Example 3.

FIG. 4 shows dissolution profiles of an active pharmaceutical ingredientfrom granules having a coating of ethylcellulose and hydroxypropylcellulose as described in Example 4.

FIG. 5 shows dissolution profiles of an active pharmaceutical ingredientfrom granules having a coating of ethylcellulose and hydroxypropylcellulose as described in Examples 2 and 4.

FIG. 6 shows dissolution profiles of an active pharmaceutical ingredientfrom granules having a coating of ethylcellulose and hydroxypropylcellulose as described in Example 5.

FIGS. 7A-7C show SEM images of granules coated with 35% wg of anethylcellulose/hydroxypropyl cellulose coating at three differentmagnifications as described in Example 6.

FIG. 8 shows dissolution profiles of an active pharmaceutical ingredientfrom granules having an ethylcellulose/hydroxypropyl cellulose coatingrepresenting different % wg as described in Example 6.

FIGS. 9A-9C show SEM images of granules coated with 35% wg of anethylcellulose/hydroxypropyl cellulose coating at three differentmagnifications as described in Example 7.

FIG. 10 shows dissolution profiles of an active pharmaceuticalingredient from granules having an ethylcellulose/hydroxypropylcellulose coating representing different % wg as described in Example 7.

FIG. 11 shows the particle size distribution of coated granulescomprising a 35% wg ethylcellulose/hydroxypropyl cellulose coating asdescribed in Example 7.

FIGS. 12A-12C show SEM images of granules coated with a 6% wgethylcellulose/hydroxypropyl cellulose seal coating at three differentmagnifications as described in Example 8.

FIGS. 13A-13C show SEM images of granules coated with 35% wg of anethylcellulose/hydroxypropyl cellulose coating at three differentmagnifications as described in Example 9.

FIG. 14 shows dissolution profiles of an active pharmaceuticalingredient from granules having an ethylcellulose/hydroxypropylcellulose coating representing different % wg as described in Example 9.

FIG. 15 shows particle size distributions of coated granules comprisinga 35% wg ethylcellulose/hydroxypropyl cellulose coating as described inExamples 7, 8, and 9.

FIG. 16 shows dissolution profiles of an active pharmaceuticalingredient from granules having a 20% wg ethylcellulose/hydroxypropylcellulose coating as described in Examples 7, 8, and 9.

FIG. 17 shows dissolution profiles of an active pharmaceuticalingredient from granules having a 30% wg ethylcellulose/hydroxypropylcellulose coating as described in Examples 7, 8, and 9.

FIG. 18 shows dissolution profiles of an active pharmaceuticalingredient from granules having a 35% wg ethylcellulose/hydroxypropylcellulose coating as described in Examples 7, 8, and 9.

FIG. 19 shows particle size distributions for an uncoated pharmaceuticalgranulation prepared as described in Example 1.

FIGS. 20A-20D show SEM images of the uncoated pharmaceutical granulationdescribed in Example 1 at different magnifications.

FIG. 21 shows the process conditions used to apply the functionalcoatings described in Examples 2-9 to the uncoated pharmaceuticalgranulation described in Example 1.

FIG. 22 shows dissolution profiles of an active pharmaceuticalingredient from granules having different % wg of anethylcellulose/hydroxypropyl cellulose coating as described in Example10.

DETAILED DESCRIPTION

For purposes of the following detailed description, it is to beunderstood that embodiments provided by the present disclosure mayassume various alternative variations and step sequences, except whereexpressly specified to the contrary. Moreover, other than in anyoperating examples, or where otherwise indicated, all numbersexpressing, for example, quantities of ingredients used in thespecification and claims are to be understood as being modified in allinstances by the term “about.”

Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired properties to beobtained by the present invention. At the very least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard variation found in theirrespective testing measurements.

Also, it should be understood that any numerical range recited herein isintended to include all sub-ranges subsumed therein. For example, arange of “1 to 10” is intended to include all sub-ranges between (andincluding) the recited minimum value of 1 and the recited maximum valueof 10, that is, having a minimum value equal to or greater than 1 and amaximum value of equal to or less than 10.

“Immediate release” refers to a pharmaceutical composition that releasessubstantially all of an active pharmaceutical ingredient into thegastrointestinal tract of a patient within less than 1 hour followingoral administration, such as within less than 50 minutes, within lessthan 40 minutes, within less than 30 minutes, within less than 20minutes, or within less than 10 minutes following oral administration.For example, an immediate release dosage form can release greater than90%, greater than 95%, or greater than 98% of the active pharmaceuticalingredient in the pharmaceutical composition into the gastrointestinaltract within less than 1 hour such as within less than 50 minutes, lessthan 40 minutes, less than 30 minutes, less than 20 minutes, or lessthan 10 minutes, following oral administration. Immediate releasepharmaceutical compositions can be appropriate to administer activepharmaceutical ingredients that are absorbed into the systemiccirculation from the upper portion of the gastrointestinal tract.

“Controlled release” pharmaceutical compositions include modifiedrelease formulations, delayed release formulations, extended releaseformulations, sustained release formulations, timed releaseformulations, pulsatile release formulations, and pH-dependent releaseformulations. These formulations are intended to release an activepharmaceutical ingredient from the pharmaceutical composition at adesired rate and/or at a desired time following oral administration by apatient and/or at a certain location or locations within thegastrointestinal tract and/or at a certain pH within thegastrointestinal tract. The United States Pharmacopeia defines amodified release system as one in which the time course or location ofdrug release or both, are chosen to accomplish objectives of therapeuticeffectiveness or convenience not fulfilled by immediate release dosageforms. A controlled release pharmaceutical composition can includeextended release and delayed-release components. A delayed releasepharmaceutical composition is one that releases a drug all at once at atime other than immediately after oral administration. A modifiedrelease formulation can include delayed-release using enteric coatings,site-specific or timed release such as for colonic delivery,extended-release including, for example, formulations capable ofproviding zero-order, first-order, or biphasic release profiles, andprogrammed release such as pulsatile and delayed extended release.

“Alkoxy” refers to a radical —OR where R is alkyl. Examples of alkoxygroups include methoxy, ethoxy, propoxy, and butoxy. An alkoxy group canbe, for example, C₁₋₆ alkoxy, C₁₋₅ alkoxy, C₁₋₄ alkoxy, C₁₋₃ alkoxy,ethoxy or methoxy.

“Alkyl” refers to a saturated, branched or straight-chain, monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane. An alkyl group can be, forexample, C₁₋₆ alkyl, C₁₋₅ alkyl, C₁₋₄ alkyl, or C₁₋₃ alkyl. An alkylgroup can be methyl, ethyl, n-propyl, iso-propyl, or tert-butyl.

“Cycloalkyl” refers to a saturated cyclic alkyl radical. A cycloalkylgroup can be, for example, C₃₋₆ cycloalkyl, C₃₋₅ cycloalkyl, C₅₋₆cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. A cycloalkyl can beselected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Alkoxycarbonyl” refers to a radical —C(═O)—O—R where R can be C₁₋₆alkyl such as C₁₋₄ alkyl, or C₁₋₃ alkyl. For example, R can be selectedfrom methyl, ethyl, n-propyl, iso-propyl, and tert-butyl.

“Cycloalkoxycarbonyl” refers to a radical —C(═O)—O—R where R can be C₃₋₈cycloalkyl, such as C₄₋₇ cycloalkyl or C₄₋₆ cycloalkyl. R can beselected, for example, from cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

“Coating” refers to the dried layer applied to granule. A “coatingcomposition” refers to the material applied to a granulation to providea coating. A coating composition comprises solids and solvents includingwater. After applying a coating composition to a granulation and dryingthe coated granulation, the coating comprises the solids content of thecoating composition.

The terms “granulation” and “granule” are used interchangeably. Agranulation comprises a plurality of granules. However, for purposes ofclarity when expressions such as “a coated granule” also refers to “acoated granulation” and “a coated granulation” refers to “a costedgranule.”

The particle size distribution parameter D90 refers to the point in thesize distribution of a sample, up to and including which, 90% of thetotal volume of material in the sample is contained. For example, for aD90 of 400 μm, 90% of the sample volume has a size of 400 μm or less D50is the size below which 50% of the total volume of material in thesample, is contained. Similarly, D10 refers to the size below which 10%of the total volume of material in the sample is contained. The volumedistribution of the sample can be determined by laser diffraction or bysieve analysis.

“Patient” refers to a mammal, for example, a human.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids andone or more protonable functional groups such as primary, secondary, ortertiary amines within the parent compound. Examples of suitableinorganic acids include hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. A salt can be formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Asalt can be formed when one or more acidic protons present in the parentcompound are replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion, or combinations thereof; orcoordinates with an organic base such as ethanolamine, diethanolamine,triethanolamine, and N-methylglucamine. A pharmaceutically acceptablesalt can be the hydrochloride salt. A pharmaceutically acceptable saltcan be the sodium salt. In compounds having two or more ionizablegroups, a pharmaceutically acceptable salt can comprise one or morecounterions, such as a bi-salt, for example, a dihydrochloride salt.

The term “pharmaceutically acceptable salt” includes hydrates and othersolvates, as well as salts in crystalline or non-crystalline form. Wherea particular pharmaceutically acceptable salt is disclosed, it isunderstood that the particular salt (e.g., a hydrochloride salt) is anexample of a salt, and that other salts may be formed using techniquesknown to one of skill in the art. Additionally, one of skill in the artwould be able to convert the pharmaceutically acceptable salt to thecorresponding compound, free base and/or free acid, using techniquesgenerally known in the art.

“Percent weight gain” or “% wg” such as in the expression “a “35% wg”refers to the increased weight of a granule or granulation followingapplication of a coating. For example, a 35% wg refers to a coatedgranule or coated granulation in which the weight of the coated granuleor coated granulation is 35% greater than the weight of the uncoatedgranule or uncoated granulation.

Dissolution profiles were measured using a USP Type 2 dissolutionapparatus and a sodium acetate buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm.

“Active pharmaceutical ingredient” refers to an active drug substance ora compound that is converted following administration into an activedrug substance such as a prodrug.

“Prodrug” refers to a derivative of a parent drug molecule that requiresa transformation within the body to provide the active drug. Prodrugsare frequently, although not necessarily, pharmacologically inactiveuntil converted to the parent drug. Prodrugs may be obtained by bondinga promoiety typically via a functional group, to a parent drug.

“Curing” a disease refers to eliminating a disease or disorder oreliminating a symptom of a disease or disorder.

“Treating” or “treatment” of a disease or disorder refers to inhibitingthe disease or disorder or one or more clinical symptoms of the diseaseor disorder, arresting the development of the disease or disorder or oneor more clinical symptoms of the disease or disorder, relieving thedisease or disorder or one or more clinical symptoms of the disease ordisorder, causing the regression of the disease or disorder or one ormore clinical symptoms of the disease or disorder, reducing the severityof one or more clinical symptom of the disease or disorder, delaying theonset of one or more clinical symptoms of the disease or disorder,and/or mitigating one or more clinical symptoms of the disease ordisorder, and/or stabilization of the disease or disorder or one or moreclinical symptoms of the disease or disorder. “Treating” or “treatment”of a disease or disorder refers to producing a clinically beneficialeffect without curing the underlying disease or disorder.

“Therapeutically effective amount” refers to the amount of a compoundsuch as active pharmaceutical ingredient that, when administered to apatient for treating a disease, or at least one of the clinical symptomsof a disease, is sufficient to affect such treatment of the disease orsymptom thereof. A “therapeutically effective amount” may varydepending, for example, on the compound, the disease and/or symptoms ofthe disease, the severity of the disease and/or symptoms of the diseaseor disorder, the age, weight, and/or health of the patient to betreated, and the judgment of the prescribing physician. Atherapeutically effective amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

“Vehicle” refers to a diluent, excipient or carrier with which acompound is administered to a patient. A vehicle can be apharmaceutically acceptable vehicle. Pharmaceutically acceptablevehicles are known in the art.

Reference is now made to pharmaceutical granulations having a functionalcoating, methods of making coated pharmaceutical granulations, andpharmaceutical compositions comprising coated pharmaceuticalgranulations. The disclosed coated pharmaceutical granulations,compositions comprising the coated pharmaceutical granulations, andmethods of making the coated pharmaceutical granulations are notintended to be limiting of the claims. To the contrary, the claims areintended to cover all alternatives, modifications, and equivalents.

Coated pharmaceutical granulations provided by the present disclosurecan be used to provide controlled release of an active pharmaceuticalingredient following oral administration to a patient. The coatedpharmaceutical granulations contain a hygroscopic, highly water-solubleactive pharmaceutical ingredient. The water-soluble activepharmaceutical ingredient can be prone to hydrolysis. The coatedpharmaceutical granulations can be used in oral pharmaceuticalcompositions. The coated pharmaceutical granulations can be used toorally administer high doses of an active pharmaceutical ingredient.

A coated pharmaceutical granulation or coated granule comprises acoating surrounding a core.

Uncoated pharmaceutical granulations are disclosed in U.S. applicationSer. No. 17/350,478 filed on Jun. 17, 2021, which is incorporated byreference in its entirety.

An uncoated pharmaceutical granulation provided by the presentdisclosure can comprise a plurality of granules, wherein the granulescomprise, for example, not less than 90 wt % of an active pharmaceuticalingredient, such as greater than 90 wt % of an active pharmaceuticalingredient, wherein the pharmaceutical granulation can be characterizedby a particle size distribution (PSD) (D50) from, from 150 μm to 500 μm,150 μm to 450 μm, 150 μm to 400 μm, from 150 μm to 350 μm, from 150 μmto 300 μm, from 200 μm to 300 μm, or from 150 μm to 250 μm, where theparticle size distribution is determined by sieve analysis; and wt % isbased on the total weight of the pharmaceutical granulation. An uncoatedgranulation can have a particle size distribution D50 less than 400 μm,less than 350 μm, less than 300 μm, less than 250 μm, or less than 200μm, where PSD is determined by sieve analysis.

An uncoated granule can comprise, for example, from 90 wt % to 99.5 wt %of an active pharmaceutical ingredient, from 90 wt % to 99 wt %, from 92wt % to 99 wt %, from 95 wt % to 99 wt %, or from 98 wt % to 99 wt % ofthe active pharmaceutical ingredient, where wt % is based on the totalweight of the uncoated granule. An uncoated granule can comprise, forexample, greater than 90 wt % of an active pharmaceutical ingredient,greater than 92 wt %, greater than 94 wt %, greater than 96 wt %,greater than 98 wt %, or greater than 99 wt % of an activepharmaceutical ingredient, wherein wt % is based on the total weight ofthe uncoated granule.

An uncoated granule can be characterized by a particle size distribution(D50), for example, from 225 μm to 275 μm, wherein the particle sizedistribution is determined by sieve analysis.

An uncoated granule can be characterized by a particle size distribution(D10), for example, from 50 μm to 150 μm; and a particle sizedistribution (D90) from 450 μm to 750 μm, where the particle sizedistribution is determined by sieve analysis.

An uncoated granule can be characterized by a particle size distribution(D10), for example, from 80 μm to 120 μm; and a particle sizedistribution (D90) from 510 μm to 650 μm, where the particle sizedistribution is determined by sieve analysis.

An uncoated granule can be characterized by a particle size distribution(D10) of 106 μm; a particle size distribution (D50) of 267 μm; and aparticle size distribution (D90) of 533 μm, where the particle sizedistribution is determined by sieve analysis.

An uncoated granule can be characterized by a particle size distribution(D50), for example, less than 500 μm, less than 450 μm, less than 400μm, less than 350 μm, less than 300 μm, less than 250 μm, or less than200 μm, wherein the particle size distribution is determined by sieveanalysis.

In addition to an active pharmaceutical ingredient, an uncoated granulecan further comprise a binder and an antistatic agent.

An uncoated granule can comprise, for example, not less than 90 wt % ofa pharmaceutically active ingredient, such as greater than 90 wt % of apharmaceutically active ingredient, from 0.1 wt % to 5 wt % of a binder,and from 0.1 wt % to 5 wt % of an antistatic agent, where wt % is basedon the total weight of the pharmaceutical granulation.

An uncoated granule can comprise, for example, from 98 wt % to 99 wt %of an active pharmaceutical ingredient; from 0.25 wt % to 0.75 wt % of abinder; and from 0.5 wt % to 1.5 wt % of an antistatic agent, where wt %is based on the total weight of the uncoated granule.

An uncoated granule can comprise, for example, 98.5 wt % of the activepharmaceutical ingredient; 0.5 wt % of a binder; and 1.0 wt % of anantistatic agent, where wt % is based on the total weight of theuncoated granule.

An uncoated granule can comprise a binder or combination of binders.

An uncoated granule can comprise, for example, less than 6 wt % of abinder, less than 5 wt %, less than 4 wt %, less than 3 wt % less than 2wt %, less than 1 wt %, less than 0.8 wt %, less than 0.6 wt %, lessthan 0.4 wt %, or less than 0.2 wt % of a binder, where wt % is based onthe total weight of the uncoated granule. An uncoated granule cancomprise, for example, from 0.1 wt % to 6.0 wt %, from 0.1 wt % to 5.0wt %, from 0.1 wt % to 4.0 wt %, from 0.1 wt % to 3.0 wt %, from 0.1 wt% to 2.0 wt %, from 0.1 wt % to 1.0 wt %, from 0.2 wt % to 0.9 wt %,from 0.2 wt % to 0.8 wt %, from 0.25 wt % to 0.75 wt %, or from 0.3 wt %to 0.7 wt % of a binder, where wt % is based on the total weight of theuncoated granule.

An uncoated granule can comprise, for example, less than 1.5 wt % of abinder, less than 1.2 wt %, less than 1.0 wt %, less than 0.8 wt %, orless than 0.6 wt % of a binder, where wt % is based on the total weightof the uncoated granule.

A binder can comprise a water-soluble polymer.

Examples of suitable binders include natural binders such as starch,pregelatinized starch, sodium alginate, and gelatin; synthetic binderssuch as polyvinyl pyrrolidone, methylcellulose, hydroxypropylmethylcellulose, polymethacrylates, sodium carboxy methyl cellulose, andpolyethylene glycol; and saccharides such as modified cellulose,hydroxypropyl cellulose, sorbitol, xylitol, and mannitol.

Examples of other suitable binders include, acacia, copovidone,carbomer, corn starch, pregelatinized starch, calcium carboxymethylcellulose, calcium cellulose glycolate, carmellosum calcium,carboxymethyl cellulose sodium, carmellose sodium, ceratonia, chitosanhydrochloride, dextrates, dextrin, ethyl cellulose, liquid glucose, guargalatomannan, guar gum, hydroxyethyl cellulose, microcrystallinecellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose,low-substituted hydroxypropyl cellulose, hydroxypropyl starch,hypromellose/hydroxypropyl methyl cellulose, Methocel®, inulin,magnesium aluminum silicate, maltodextrin, methylcellulose, polyethyleneglycol, polyethylene oxide, povidone, sodium alginate, starch,pregelatinized starch, sucrose, compressible sugar, zein, gelatin,polymethacrylates, sorbitol, glucose, and sodium alginate.

A binder can comprise hydroxypropyl cellulose, hydroxypropylmethylcellulose or a combination thereof.

In an uncoated pharmaceutical granulation, the binder can comprisehydroxypropylmethyl cellulose. In certain uncoated pharmaceuticalgranulations, the binder does not comprise hydroxypropylmethylcellulose.

In an uncoated pharmaceutical granulation, the binder can comprisehydroxypropyl cellulose.

An uncoated granule can comprise an antistatic agent or a combination ofantistatic agents.

An uncoated granule can comprise, for example, less than 6 wt % of anantistatic agent, less than 5 wt %, less than 4 wt %, less than 3 wt %,less than 2.5 wt %, less than 2.0 wt %, less than 1.25 wt %, less than 1wt %, less than 0.75 wt %, less than 0.5 wt %, or less than 0.25 wt % ofan antistatic agent, where wt % is based on the total weight of theuncoated granule. An uncoated granule can comprise, for example, from0.1 wt % to 2.0 wt % of an antistatic agent, from 0.2 wt % to 1.8 wt %,from 0.5 wt % to 1.50 wt %, or from 0.75 wt % to 1.25 wt % of anantistatic agent, where wt % is based on the total weight of theuncoated granule.

An uncoated granule can comprise a suitable antistatic agent.

Examples of suitable antistatic agents include silica, talc, magnesiumstearate, sodium stearyl fumarate, and combinations of any of theforegoing.

An antistatic agent can comprise silica such as hydrophilic silica, suchas hydrophilic fumed silica.

In an uncoated pharmaceutical granulation, the antistatic agent cancomprise hydrophilic fumed silica.

An antistatic agent can comprise, for example, hydrophilic fumed silicasuch as Aerosil® fumed silica from Evonik Industries, Cab-o-sil® fumedsilica from Cabot Corporation, or HDK® fumed silica from BrenntagSolutions Group.

An antistatic agent can comprise Aerosil® 200 available from EvonikIndustries.

A hydrophilic fumed silica can have a specific surface area (BET from100 m²/g to 300 m²/g such as from 175 m²/g to 225 m²/g, a pH value from3.7 to 4.5 in a 4% aqueous dispersion, a loss on drying in 2 hours at105° C. of less than or equal to 1.5%, a tamped density from about 40g/L to 60 g/L, and an SiO2 content greater than 99.8% based on ignitedmaterial.

In certain granulations, the antistatic agent comprises talc.Pharmaceutical grade talc is available, for example, from Imerys Talcand Elementis PLC.

In certain uncoated granulations, the antistatic agent does not comprisetalc. In certain uncoated granulations, the binder does not comprisehydroxypropylmethyl cellulose and the antistatic agent does not comprisetalc.

In addition to an active pharmaceutical ingredient, a binder, and anantistatic agent a granule can comprise one or more excipients such as,for example, flow control agents, lubricants, disintegrants, fillers,compression aids, surfactants, diluents, colorants, buffering agents,glidants, and combinations of any of the foregoing.

An uncoated granule can comprise, for example, less than 3 wt % of theone or more excipients, less than 2 wt %, less than 1 wt %, or less than0.5 wt % of the one or more excipients, where wt % is based on the totalweight of the granule. A granule can comprise, for example, from 0 wt %to 3% of one or more excipients, from 0.1 wt % to 3 wt %, from 0.5 wt %to 2 wt % or from 1 wt % to 2 wt % of one or more excipients, where wt %is based on the total weight of the granule.

Examples of suitable flow control agents or glidants include magnesiumstearate, fumed silica (colloidal silicon dioxide), starch, talc, andcombinations of any of the foregoing.

Examples of suitable lubricants include magnesium stearate, stearicacid, calcium stearate, hydrogenated castor oil, hydrogenated vegetableoil, light mineral oil, magnesium stearate, mineral oil, polyethyleneglycol, sodium benzoate, sodium stearyl fumarate, zinc stearate, andcombinations of any of the foregoing.

Examples of suitable disintegrants include citric acid croscarmellosesodium, colloidal silicone dioxide, crospovidone, sodium starchglycolate, microcrystalline cellulose, pregelatinized starch, andcombinations of any of the foregoing.

A surfactant can comprise an ionic surfactant or a non-ionic surfactant.Examples of suitable ionic surfactants include docusate sodium (dioctylsulfosuccinate sodium salt), sodium lauryl sulfate, and combinations ofany of the foregoing. Examples of suitable non-ionic surfactants includepolyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamers,polysorbate, sorbitan esters, glyceryl monooleate, and combinations ofany of the foregoing.

Examples of suitable fillers and compression aids include lactose,calcium carbonate, calcium sulfate, compressible sugars, dextrates,dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide,maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose,sucrose, and combinations of any of the foregoing.

An uncoated pharmaceutical granulation comprises a plurality of uncoatedgranules. To form a coated pharmaceutical granulation, a functionalcoating and optional seal coat can be applied to the uncoatedpharmaceutical granulation. The coated granulation comprises a pluralityof coated granules. The coated granules comprise a functional coatingsurrounding the uncoated granule, and which can be referred to as thecore of the coated granule.

An uncoated pharmaceutical granulation provided by the presentdisclosure comprises a plurality of granules, where the granules cancomprise, for example, greater than 85 wt % of an active pharmaceuticalingredient, greater than 90 wt %, or greater than 95 wt % of an activepharmaceutical ingredient, where wt % is based on the total weight ofthe uncoated granules; and the uncoated pharmaceutical granulation ischaracterized by a particle size distribution (D50), the mediandiameter), for example, from 150 μm to 450 μm.

An uncoated granule can comprise a high loading of an activepharmaceutical ingredients or a high loading of a combination of activepharmaceutical ingredients. For example, an uncoated granule cancomprise greater than 85 wt %, greater than 90 wt %, greater than 95 wt%, greater than 96 wt %, greater than 97 wt %, greater than 98 wt % orgreater than 99 wt % of an active pharmaceutical ingredient, where wt %is based on the total weight of the uncoated granule. An uncoatedgranule can comprise, for example, from 85 wt % to 99.5 wt % of anactive pharmaceutical ingredient, from 90 wt % to 99.5 wt %, from 95 wt% to 99.5 wt %, from 96 wt % to 99 wt %, from 97 wt % to 99 wt %, orfrom 98 wt % to 99 wt % of an active pharmaceutical ingredient, where wt% is based on the total weight of the uncoated granule.

An uncoated granule can comprise an active pharmaceutical ingredienthaving a high aqueous solubility.

For example, an active pharmaceutical ingredient can have an aqueoussolubility greater than 100 mg/mL, greater than 150 mg/mL, greater than200 mg/mL, greater than 250 mg/mL, greater than 300 mg/mL, greater than350 mg/mL, greater than 400 mg/mL, greater than 500 mg/mL, greater than600 mg/mL An active pharmaceutical ingredient can have an aqueoussolubility, for example, from 100 mg/mL to 600 mg/mL, from 200 mg/mL to500 mg/mL, or from 250 mg/mL to 450 mg/mL.

Aqueous solubility is determined by high pressure liquid chromatography(HPLC).

Examples of active pharmaceutical ingredients having a water solubilitygreater than 100 mg/mL include acetohydroxamic acid, aliskiren,amifostine, aminocaproic acid, aminolevulinic acid, aminophylline,ascorbic acid, benzethonium, benzphetamine, betazole, bretylium,bromotheophylline, brompheniramine, bronopol, bupropion hydrochloride,folinic acid, captopril, carbamoylcholine, chloral hydrate, cidofovir,citrulline, clavulanic acid, clindamycin, codeine phosphate,cycloserine, cysteamine, cytarabine, d-glucose, dinoprost tromethamine,d-serine, dyphylline, edetic acid, emtricitabine, esketaminehydrochloride, arketamine hydrochloride, ethambutol hydrochloride,ferrous bisglycinate, flurazepam, fomepizole, framycetin, gabapentin,gamma-aminobutyric acid, gemifloxacin, gentamicin, gluconic acid,gluconolactone, glucosamine, glutathione, ibandronate, ibutilide,isoniazid, ketorolac, lactitol, lactose, lactulose, levamisolehydrochloride, levetiracetam, levocarnitine, lisdexamfetamine, mannitol,metformin hydrochloride, methenamine, methimazole, methylaminolevulinate, migalastat hydrochloride, miglustat, nalmefenehydrochloride, naltrexone hydrochloride, neostigmine bromide,netilmicin, nicotinamide, nicotine, nitrofural, norfloxacin, ornithine,oxycodone, penicillamine, pentoxyverine, phenformin, phenylephrine,phenylpropanolamine, pidolic acid, piperazine, piracetam, pregabalin,procarbzine hydrochloride, promethazine hydrochloride, pyridoxine,pyruvic acid, ranitidine hydrochloride, rolitetracycline, ropinirole,scopolamine, selenomethionine, sodium ascorbate, sodium oxybate,terbutraline, thiamine hydrochloride, tobramycin, tranexamic acid,tromethamine salt, valacyclovir, and venlafaxine hydrochloride.

An active pharmaceutical ingredient having a water solubility greaterthan 100 mg/mL can include salt forms, hydrates, and/or solvates of aparent active pharmaceutical ingredient having a water solubilitygreater than 100 mg/mL where the parent active pharmaceutical ingredienthas a water solubility less than 100 mg/mL.

An active pharmaceutical ingredient can comprise γ-hydroxybutyric acidor a derivative of γ-hydroxybutyric acid or a pharmaceuticallyacceptable salt of any of the foregoing. γ-Hydroxybutyric acid has thestructure of Formula (1):

A derivative of γ-hydroxybutyric acid can have the structure of Formula(2):

or a pharmaceutically acceptable salt thereof, where,

-   -   R¹ can be selected from hydrogen and C₁₋₆ alkyl; and    -   each of R² and R³ can independently be selected from hydrogen,        C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, and C₃₋₈ cycloalkoxycarbonyl.

In compounds of Formula (2), R¹ can be selected from hydrogen and C₁₋₃alkyl.

In compounds of Formula (2), R¹ can be selected from hydrogen, methyl,ethyl, n-propyl, and iso-propyl.

In compounds of Formula (2), R¹ can be hydrogen.

In compounds of Formula (2), R¹ can be methyl.

In compounds of Formula (2), R¹ can be iso-propyl.

In compounds of Formula (2), at least one of R² and R³ can be selectedfrom hydrogen and C₁₋₃ alkyl.

In compounds of Formula (2), each of R² and R³ can independently beselected from hydrogen and C₁₋₃ alkyl.

In compounds of Formula (2), each of R² and R³ can be hydrogen.

In compounds of Formula (2),

R¹ can be selected from hydrogen and C₁₋₃ alkyl; and

R² can be selected from C₁₋₆ alkoxycarbonyl and C₅₋₆cycloalkoxycarbonyl.

In compounds of Formula (2),

each of R² and R³ can be hydrogen; and

R¹ can be selected from hydrogen and C₁₋₃ alkyl.

In compounds of Formula (2),

each of R² and R³ can be hydrogen; and

R¹ can be selected from hydrogen, methyl, ethyl, n-propyl, andiso-propyl.

In compounds of Formula (2),

each of R² and R³ can be hydrogen; and

R¹ can be selected from hydrogen, methyl, and iso-propyl.

In compounds of Formula (2), the carbon atom to which R¹ is bonded canbe in the (R)-configuration.

In compounds of Formula (2), the carbon atom to which IV is bonded canbe in the (S)-configuration.

A compound of Formula (2) can be selected from:

-   4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(glycyloxy)butanoic acid;-   4-((D-valyl)oxy)butanoic acid;-   4-((L-alanyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid;-   4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid;-   4-((L-valyl)oxy)butanoic acid;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

A compound of Formula (2) can be 4-((L-valyl)oxy)butanoic acid (2a) or apharmaceutically acceptable salt thereof:

A compound of Formula (2) can be 4-(glycyloxy)butanoic acid (2b) or apharmaceutically acceptable salt thereof:

A compound of Formula (2) can be 4-((L-alanyl)oxy)butanoic acid (2c) ora pharmaceutically acceptable salt thereof:

Compounds of Formula (2)-(2c) are prodrugs of γ-hydroxybutyric acid,which when orally administered. provide γ-hydroxybutyric acid in theblood of a patient. Compounds of Formula (2)-(2c) exhibit a relativeoral bioavailability of γ-hydroxybutyric acid in a patient of greaterthan 10% F, greater than 20% F, greater than 30% F, greater than 40% F,greater than 50% F, or greater than 60% F.

Before forming into granules, the active pharmaceutical ingredient canhave a low bulk density.

An active pharmaceutical ingredient can have a bulk density, forexample, less than 0.20 g/mL, less than 0.30 g/mL, less than 0.40 g/mL,less than 0.50 g/mL, less than 0.6 g/mL, less than 0.7 g/mL, less than0.8 g/mL, or less than 1.0 g/mL.

An active pharmaceutical ingredient can have a bulk density, forexample, from 0.15 g/mL to 1.0 g/mL, from 0.15 g/mL to 8 g/mL, from 0.15g/mL to 0.6 g/mL, from 0.15 g/mL to 0.4 g/mL, from 0.15 g/mL to 0.33g/mL, from 0.16 g/mL to 0.32 g/mL, from 0.17 g/mL to 0.31 g/mL, from0.18 g/mL to 0.30 g/mL, from 0.19 g/mL to 0.29 g/mL, or from 0.20 g/mLto 0.28 g/mL.

An active pharmaceutical ingredient can have a specific surface area,for example, from 200 m²/kg to 1200 m²/kg, such as from 400 m²/kg to1000 m²/kg, wherein the specific surface area is determined using laserdiffraction. An active pharmaceutical ingredient can have a specificsurface area, for example, greater than 200 m²/kg, greater than 400m²/kg, greater than 600 m²/kg, greater than 800 m²/kg, or greater than1200 m²/kg, where the specific surface area is determined by laserdiffraction.

An active pharmaceutical ingredient can have a particle sizedistribution characterized, for example, by a D10 from 1 μm to 3 μm, aD50 from 6.5 μm to 8.5 μm, and a D90 from 15 μm to 17 μm, where particlesize distribution is measured by laser diffraction.

An active pharmaceutical ingredient can have a particle sizedistribution, for example, as substantially shown in any one of FIGS. 11and 15.

An active pharmaceutical ingredient can be jet milled to reduce theparticle size.

A jet-milled active pharmaceutical ingredient can have a particle sizedistribution, for example, less than 30 μm, less than 25 μm, less than20 μm, or less than 15 μm.

An uncoated pharmaceutical granulation or uncoated granule can comprise,for example, from 95.0 wt % to 99.5 wt % of the active pharmaceuticalingredient; from 0.1 wt % to 1.0 wt % of a binder; and from 0.1 wt % to2.0 wt % of an antistatic agent, wherein wt % is based on the totalweight of the uncoated pharmaceutical granulation or uncoated granule.

An uncoated pharmaceutical granulation or uncoated granule can comprise,for example, from 98 wt % to 99 wt % of the active pharmaceuticalingredient; from 0.25 wt % to 0.75 wt % of a binder; and from 0.5 wt %to 1.5 wt % of an antistatic agent, wherein wt % is based on the totalweight of the uncoated pharmaceutical granulation or uncoated granule.

An uncoated pharmaceutical granulation or uncoated granule can comprise,for example, from 98.25 wt % to 98.75 wt % of the active pharmaceuticalingredient; from 0.33 wt % to 0.65 wt % of a binder; and from 0.74 wt %to 1.25 wt % of an antistatic agent, wherein wt % is based on the totalweight of the uncoated pharmaceutical granulation or uncoated granule.

An uncoated pharmaceutical granulation or uncoated granule can comprise,for example, from 85.0 wt % to 99.5 wt % of the active pharmaceuticalingredient; from 0.1 wt % to 8.0 wt % of a binder; and from 0.1 wt % to8.0 wt % of an antistatic agent, wherein wt % is based on the totalweight of the uncoated pharmaceutical granulation or uncoated granule.

An uncoated pharmaceutical granulation or granule can comprise, forexample, from 85.0 wt % to 95.0 wt % of the active pharmaceuticalingredient; from 2.0 wt % to 7.0 wt % of a binder; and from 2.0 wt % to7.0 wt % of an antistatic agent, wherein wt % is based on the totalweight of the uncoated pharmaceutical granulation or uncoated granule.

An uncoated pharmaceutical granulation or granule can comprise, forexample, from 87.0 wt % to 93.0 wt % of the active pharmaceuticalingredient; from 3.0 wt % to 7.0 wt % of a binder; and from 3.0 wt % to7.0 wt % of an antistatic agent, wherein wt % is based on the totalweight of the uncoated pharmaceutical granulation or uncoated granule.

An uncoated granulation can consist of an active pharmaceuticalingredient, a binder, and an antistatic agent. In addition to an activepharmaceutical ingredient, an uncoated granulation can consist of abinder consisting of hydroxypropyl cellulose and/or an antistatic agentconsisting of talc. An uncoated granulation can consist of an activepharmaceutical ingredient selected from a compound of Formula (2), abinder wherein the binder consists of hydroxypropyl cellulose, and anantistatic agent wherein the antistatic agent consists of talc. Anuncoated granulation can have trace amounts of water. In certainpharmaceutical compositions and granulations, the active pharmaceuticalingredient does not include 4-((L-valyl)oxy)butanoic acid (2a) or apharmaceutically acceptable salt thereof:

An uncoated granule provided by the present disclosure can becharacterized by a sphericity, for example, from 0.90 to 1, such as from0.91 to 0.99, or from 0.92 to 0.98, where sphericity is determined usingwet dispersion particle shape methods or by dynamic image analysis. Anuncoated granule provided by the present disclosure can be characterizedby a sphericity, for example, greater than 0.90, greater than 0.91,greater than 0.92, greater than 0.93, greater than 0.94, or greater than0.95.

An uncoated pharmaceutical granulation provided by the presentdisclosure can be comprise a plurality of granules characterized by amode sphericity, for example, from 0.90 to 1, such as from 0.91 to 0.99,or from 0.92 to 0.98, where sphericity is determined using wetdispersion particle shape methods or by dynamic image analysis. Anuncoated pharmaceutical granulation provided by the present disclosurecan comprise a plurality of granules characterized by an averagesphericity, for example, greater than 0.94, greater than 0.95, greaterthan 0.96, greater than 0.97, greater than 0.98, or greater than 0.99.

Uncoated granules provided by the present disclosure are solid and arecharacterized by a substantially homogeneous composition throughout thegranule.

For high dose active pharmaceutical ingredients, especially whenreconstituted as a suspension before administration, to improvepalatability it can be useful that the granules have a small meandiameter.

An uncoated pharmaceutical granulation provided by the presentdisclosure can be characterized, for example, by a particle sizedistribution (D50) from 75 μm to 500 μm, from 75 μm to 450 μm, from 75μm to 450 μm, from 100 μm to 400 μm, from 150 μm to 350 μm, such as from175 μm to 325 μm, from 200 μm to 300 μm, or from 225 μm to 275 μm. Anuncoated pharmaceutical granulation provided by the present disclosurecan be characterized, for example, by a particle size distribution (D50)of less than 400 μm, less than 360 μm, or less than 320 μm.

An uncoated pharmaceutical granulation can be characterized, forexample, by a particle size distribution (D10) from 50 μm to 150 μm,from 60 μm to 140 μm, from 70 μm, to 120 μm, from 80 μm to 110 μm, from50 μm to 150 μm, or from 50 μm to 200 μm. An uncoated pharmaceuticalgranulation can be characterized, for example, by a particle sizedistribution (D10) of less than 200 μm, less than 160 μm, or less than120 μm.

An uncoated pharmaceutical granulation can be characterized, forexample, by a particle size distribution (D90) from 450 μm to 800 μm,450 μm to 750 μm, from 475 μm to 725 μm, from 500 μm to 700 μm, from 525μm to 675 μm, or from 550 μm to 650 μm. An uncoated pharmaceuticalgranulation can be characterized, for example, by a particle sizedistribution (D90) of less than 800 μm, less than 700 μm, less than 600μm, or less than 500 μm.

An uncoated pharmaceutical granulation can be characterized, forexample, by a particle size distribution (D10) from 50 μm to 150 μm; aparticle size distribution (D50) from 220 μm to 320 μm; and a PSD (D90)from 480 μm to 560 μm. An uncoated granulation can be characterized by aparticle size distribution D50, for example, less than 500 μm, less than450 μm, less than 400 μm, less than 350 μm, less than 300 μm less than250 μm, or less than 200 μm.

An uncoated pharmaceutical granulation can be characterized, forexample, by a particle size distribution (D10) from 60 μm to 140 μm; aparticle size distribution (D50) from 230 μm to 310 μm; and a particlesize distribution (D90) from 490 μm to 550 μm.

An uncoated pharmaceutical granulation can be characterized, forexample, by a particle size distribution (D10) from 70 μm to 130 μm; aparticle size distribution (D50) from 240 μm to 300 μm; and a particlesize distribution (D90) from 500 μm to 540 μm.

Examples of particle size distributions for uncoated granulationsprovided by the present disclosure is shown in FIG. 18.

A particle size distribution can be determined by laser diffraction orby sieve analysis.

An uncoated pharmaceutical granulation can have a bulk density, forexample, greater than 0.40 g/mL, greater than 0.50 g/mL, greater than0.60 g/mL, greater than 0.90 g/mL, greater than 1.10 g/mL, greater than1.30 g/mL, or greater than 1.50 g/mL.

A uncoated pharmaceutical granulation can have a bulk density, forexample, from 0.40 g/mL to 1.60 g/mL, from 0.40 g/mL to 1.20 g/mL, from0.40 g/mL to 0.80 g/mL, from 0.50 g/mL to 1.60 g/mL, from 0.50 g/mL to1.40 g/mL, from 0.50 g/mL to 1.20 g/mL, from 0.60 g/mL to 1.60 g/mL,from 0.70 g/mL to 1.50 g/mL, from 0.80 g/mL to 1.40 g/mL, or from 1.00g/mL to 1.20 g/mL.

An uncoated pharmaceutical granulation can have a bulk density, forexample, from 0.60 g/mL to 1.60 g/mL, from 0.70 g/mL to 1.50 g/mL, from0.80 g/mL to 1.40 g/mL, or from 1.00 g/mL to 1.20 g/mL.

Bulk density can be determined using a bulk density cylinder.

An uncoated pharmaceutical granulation or granule can have a bulkdensity, for example, from 0.5 g/mL to 1.0 g/mL, from 0.5 g/mL to 0.9g/mL, from 0.5 g/mL to 0.8 g/mL, from 0.5 g/mL to 0.7 g/mL, or from 0.6g/mL to 0.7 g/mL. An uncoated pharmaceutical granulation or granule canhave a bulk density, for example, greater than 0.5 g/mL, greater than0.6 g/mL, greater than 0.7 g/mL, greater than 0.8 g/mL, or greater than0.9 g/mL.

Scanning electron micrograph (SEM) images of examples of uncoatedgranules provided by the present disclosure are shown in FIGS. 20A-20Dwith magnifications of 110×, 220×, 1,000×, and 2,000×, respectively. Theuncoated granules shown in FIGS. 20A-20D are characterized bysubstantially smooth surfaces.

Smooth granule surfaces facilitate the ability to coat the granules witha thin, continuous functional coating having a substantially homogeneousthickness. The qualities of the coating can be important for controlledrelease formulations. For example, rough and/or porous surfaces tend torequire a significantly higher amount of a functional coating to achievea comparable release profile to smooth surfaces. In addition, coatingsof rough and/or porous surfaces can lead to a variable dissolution orrelease profile.

An uncoated pharmaceutical granulation provided by the presentdisclosure can be characterized by a loss on drying (LOD), for example,from 0.92 to 0.98, from 0.93 to 0.97, or from 0.94 to 0.96. The LODrepresents removal of water incorporated into the granules duringpreparation of the uncoated pharmaceutical.

LOD is determined by thermogravimetric analysis.

An uncoated pharmaceutical granulation provided by the presentdisclosure can be characterized by a friability value, for example, from0% to 2%. Granules with low friability are easier to coat than aregranules with high friability. Friability is defined as the amount ofgranules having a diameter less than 75 μm that are generated bysubjecting a granulation to a sonic sifter operated at a vibrationamplitude of 8 corresponding to 3,600 sonic energy pulses per minute forat least 2 minutes.

An uncoated pharmaceutical granulation provided by the presentdisclosure can have a friability, for example, of 1.02% where friabilityis determined using a sonic sifter.

Methods of making uncoated pharmaceutical granulations containing a highloading of highly water soluble active pharmaceutical ingredients aredisclosed in U.S. application Ser. No. 17/350,478 filed on Jun. 17,2021.

Coated pharmaceutical granulations provided by the present disclosurecan comprise a plurality of uncoated granules coated with a functionalcoating. A functional coating can comprise, for example, an immediaterelease coating, a controlled release coating, a modified releasecoating, a sustained release coating, a pH-release coating, a pulsatilerelease coating, a timed-release coating, or a delayed release coating.A functional coating can be configured to release an activepharmaceutical ingredient from a coated granule or core, for example,over an intended period of time following ingestion and/or within anintended region of the gastrointestinal tract.

A coated pharmaceutical granule provided by the present disclosure cancomprise one or more functional coatings.

Each of the one or more functional coatings can independently have anaverage thickness, for example, less than 300 μm, less than 200 μm, lessthan 150 μm, less than 100 μm, less than 50 μm, less than 40 μm, lessthan 30 μm, less than 25 μm, less than 20 μm, less than 10 μm, or lessthan 5 μm. Each of the one or more functional coatings can independentlyhave an average thickness, for example, from 5 μm to 300 μm, from 5 μmto 200 μm, from 5 μm to 100 μm, from 5 μm to 50 μm, from 5 μm to 40 μm,from 5 μm to 30 μm, from 5 μm to 25 μm, from 5 μm to 20 μm, or from 5 μmto 15 μm.

A coated granule can comprise, for example, less than 50 wt % of afunctional coating, less than 45 wt % of a functional coating, less than40 wt %, less than 30 wt %, less than 20 wt %, or less than 10 wt % of afunctional coating, where wt % is based on the total weight of thecoated granule.

A coated granule can comprise, for example, from 1 wt % to 50 wt % of afunctional coating, from 5 wt % to 50 wt %, from 10 wt % to 45 wt %, orfrom 15 wt % to 40 wt % of a functional coating, where wt % is based onthe total weight of the coated granule.

Dosage forms containing a highly water-soluble active pharmaceuticalingredient can have a thick coating to reduce the release rate of theactive pharmaceutical ingredient and/or increase the storage stabilityof the active pharmaceutical ingredient by minimizing or preventingingress of moisture.

A coated granule or coated granulation can comprise, for example,greater than 50 wt % of an active pharmaceutical ingredient, greaterthan 55 wt %, greater than 60 wt %, greater than 70 wt %, greater than80 wt %, or greater than 85 wt % of an active pharmaceutical ingredient,where wt % is based on the total weight of the coated granule or coatedgranulation.

A coated granule or coated granulation comprising a plurality of coatedgranules can comprise, for example, from 50 wt % to 95 wt % of an activepharmaceutical ingredient, from 55 wt % to 90 wt %, from 60 wt % to 85wt %, from 65 wt % to 80 wt % or from 70 wt % to 75 wt % of an activepharmaceutical ingredient, where wt % is based on the total weight ofthe coated granule or coated granulation.

A coated granule can comprise a core, i.e., uncoated granule, and afunctional coating surrounding the cores. A coated granule can comprise,for example, from 55 wt % to 90 wt % of a core, and from 10 wt % to 45wt % of the functional coating, where wt % is based on the total weightof the coated granule. A coated granule can comprise, for example, from60 wt % to 85 wt % of a core, and from 15 wt % to 40 wt % of thefunctional coating, where wt % is based on the total weight of thecoated granule.

A functional coating can comprise a matrix polymer or combination ofmatrix polymers. A combination of matrix polymers can comprise awater-insoluble polymer and/or a water-soluble or pore forming polymer.The combination of matrix polymers can be selected to provide for adesired release profile of an active pharmaceutical ingredient in thegastrointestinal tract.

A functional coating can comprise, for example, from 55 wt % to 85 wt %of a matrix polymer, from 60 wt % to 85 wt %, from 65 wt % to 80 wt %,or from 70 wt % to 80 wt %, of a matrix polymer, where wt % is based onthe total weight of the functional coating.

A functional coating can comprise, for example less than 85 wt % of amatrix polymer, less than 80 wt %, less than 75 wt %, less than 70 wt %,or less than 65 wt % of a matrix polymer, where wt % is based on thetotal weight of the functional coating.

A functional coating can comprise, for example, greater than 60% of amatrix polymer, greater than 65 wt %, greater than 70 wt %, greater than75 wt %, or greater than 80 wt % of a matrix polymer, where wt % isbased on the total weight of the functional coating.

A matrix polymer can comprise a water-insoluble polymer or combinationof water-insoluble polymers.

Examples of suitable water insoluble polymers include ethylcellulose,polyvinyl acetates, polyacrylates, and polymethacrylates.

A water insoluble polymer can be ethylcellulose.

A water insoluble polymer such as ethylcellulose can have an averagemolecular weight, for example, from 25,000 Daltons, to 300,000 Daltons,such as from 50,000 Daltons to 200,000 Daltons, from 50,000 Daltons to150,000 Daltons, or from 50,000 Daltons to 100,000 Daltons.

A water insoluble polymer such as ethylcellulose can have a viscosity,for example, less than 100 mPa×sec, less than 75 mPa×sec, less than 50mPa×sec, less than 25 mPa×sec, less than 20 mPa×sec, or less than 15mPa×sec, as determined using a Brookfield viscometer in an 80:20 mixtureof toluene/ethanol.

Examples of suitable ethylcellulose polymers include Aqualon® T10 Pharm,N7 Pharm, N10 Pharm, N14 Pharm, N22 Pharm, N50 Pharm, and N100 Pharmpolymers, available from Ashland. Other examples of suitableethylcellulose polymers include Ethocel® Standard 7, Standard 10,Standard 14, Standard 20 polymers, available from Dupont.

A functional coating can comprise, for example, from 65 wt % to 100 wt %of a water insoluble polymer, from 65 wt % to 90 wt %, or from 70 wt %to 80 wt % of a water insoluble polymer, wherein wt % is based on thetotal weight of the functional coating. A functional coating cancomprise, for example, greater than 65 wt % of a water insoluble polymersuch as ethylcellulose, greater than 70 wt %, greater than 75 wt %, orgreater than 80 wt % of a water insoluble polymer, wherein wt % is basedon the total weight of the functional coating.

A matrix polymer can comprise, for example, from 85 wt % to 100 wt % ofa water-insoluble polymer, from 90 wt % to 100%, from 92 wt % to 98 wt%, from 91 wt % to 99 wt %, from 92 wt % to 98 wt %, or from 93 wt % to97 wt % of a water-insoluble polymer, where wt % is based on the totalweight of the matrix polymer. A matrix polymer can comprise, forexample, greater than 85 wt % of a water insoluble polymer, greater than90 wt %, greater than 92 wt %, greater than 94 wt %, greater than 96 wt%, or greater than 98 wt % of a water insoluble polymer, where wt % isbased on the total weight of the matrix polymer. A matrix polymer cancomprise, for example less than 100 wt % of a water insoluble polymer,less than 98 wt %, less than 96 wt %, less than 94 wt %, less than 92 wt%, less than 90 wt %, or less than 85 wt % of a water insoluble polymer,where wt % is based on the total weight of the matrix polymer.

A matrix polymer can comprise a pore forming polymer or combination ofpore-forming polymers. A pore forming polymer refers to a water-solublepolymer.

Examples of pore formers include water-soluble polymers, polymers thatswell or expand such as carbomers, and polymers soluble in gastric fluidsuch as cellulose acetate phthalate, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, methacrylic acid-methyl methacrylatecopolymers, and polyvinyl acetate phthalate. A pore forming polymer canincrease the permeability of a functional coating under intendedconditions.

A matrix polymer can comprise a water-soluble polymer or combination ofwater-soluble polymers.

Examples of suitable water-soluble polymers include hydroxypropylcellulose, polyvinyl alcohol, hydroxypropylmethyl cellulose,hydroxypropylethyl cellulose, polyvinylpyrrolidone, polyethylene glycol,polyvinyl alcohol, povidone, crospovidone, and poloxamer.

A water-soluble polymer such as hydroxypropyl cellulose can have anaverage molecular weight, for example, less than 1,000,000 Daltons, lessthan 800,000 Daltons, less than 600,000 Daltons, less than 400,000Daltons, less than 200,000 Daltons, less than 100,000 Daltons, or lessthan 50,0000 Daltons.

A water-soluble polymer such as hydroxypropyl cellulose can have aviscosity, for example, less than 7,000 mPa×sec, less than 5,000mPa×sec, less than 3,000 mPa×sec, or less than 1,000 mPa×sec, asdetermined using a Brookfield viscometer in an 80:20 mixture oftoluene/ethanol.

Examples of suitable hydroxypropyl cellulose polymers include Klucel® HFPharm, MF Pharm, GF Pharm μF Pharm, LF Pharm, EF Pharm, and ELF Pharmpolymers, available from Ashland.

Examples of suitable hydroxypropylmethyl cellulose polymers includePharmacoat® 603, 645, 606 and 615 polymers, available from Shin-EtsuChemical Co.

A matrix polymer can comprise, for example, from 0 wt % to 20 wt % of awater-soluble polymer, from 0 wt % to 10 wt %, from 0.5 wt % to 20 wt %,from 1 wt % to 10 wt %, from 1 wt % to 8 wt %, from 2 wt % to 7 wt %,from 2 wt % to 6 wt %, or from 4 wt % to 6 wt %, of a water-solublepolymer, where wt % is based on the total weight of the matrix polymer.A matrix polymer can comprise, for example, greater than 0 wt % of awater-soluble polymer, greater than 2 wt %, greater than 4 wt %, greaterthan 6 wt %, greater than 8 wt %, greater than 10 wt %, or greater than15 wt % of a water-soluble polymer, where wt % is based on the totalweight of the matrix polymer. A matrix polymer can comprise, forexample, less than 20 wt %, less than 15 wt %, less than 10 wt % of awater-soluble polymer, less than 8 wt %, less than 6 wt %, less than 4wt %, or less than 2 wt % of a water-soluble polymer, where wt % isbased on the total weight of the matrix polymer. In certain functionalcoatings, the matrix polymer does not include a water-soluble polymersuch as hydroxypropyl cellulose

A matrix polymer can comprise, for example, from 90 wt % to 100 wt % ofa water-insoluble polymer and from 0 wt % to 10 wt % of a water-solublepolymer; from 92 wt % to 98 wt % of a water-insoluble polymer and from 2wt % to 8 wt % of a water-soluble polymer; or from 94 wt % to 96 wt % ofa water-insoluble polymer and from 4 wt % to 6 wt % of a water-solublepolymer, where wt % is based on the total weight of the matrix polymer.

A functional coating can comprise, for example, from 65 wt % to 90 wt %of a water-insoluble polymer and from 1 wt % to 10 wt % of awater-soluble polymer; from 70 wt % to 85 wt % of a water-insolublepolymer and from 2 wt % to 8 wt % of a water-soluble polymer; or from 72wt % to 83 wt % of a water-insoluble polymer and from 3 wt % to 7 wt %of a water-soluble polymer, where wt % is based on the total weight ofthe functional coating.

In addition to a matrix polymer or combination of matrix polymers, afunctional coating can comprise, for example, a plasticizing agent, ananti-static, an anti-tacking agent, a colorant or pigment, a glidant, aviscosity modifier, or a combination of any of the foregoing.

A functional coating can comprise an antistatic agent or combination ofantistatic agents.

An antistatic agent can be useful to minimize or prevent agglomerationof the granules during application of the functional coating.

Examples of suitable antistatic agents include talc, magnesium stearate,and silicon dioxide.

An antistatic agent can comprise talc.

An antistatic agent can comprise magnesium stearate. In certainfunctional coatings, the antistatic agent does not comprise magnesiumstearate.

A functional coating can comprise, for example, from 10 wt % to 20 wt %of an antistatic agent, such as from 12 wt % to 18 wt %, or from 14 wt %to 16 wt % of an antistatic agent, where wt % is based on the totalweight of the functional coating. A functional coating can comprise, forexample, less than 20 wt % of an antistatic agent, less than 18 wt %,less than 16 wt %, less than 14 wt % or less than 12 wt % of anantistatic agent, where wt % is based on the total weight of thefunctional coating. A functional coating can comprise, for example,greater than 10 wt % of an antistatic agent, greater than 12 wt %,greater than 14 wt %, greater than 16 wt %, or greater than 18 wt % ofan antistatic agent, where wt % is based on the total weight of thefunctional coating.

A functional coating can comprise a plasticizer or combination ofplasticizers.

A plasticizer can be useful to provide a functional coating having auniform thickness.

Examples of suitable plasticizers include dibutyl sebacate, polyethyleneglycol, triacetin, and triethyl citrate.

A plasticizer can comprise dibutyl sebacate.

In certain functional coatings, the functional coating does not comprisea plasticizer.

A functional coating can comprise, for example, from 0 wt % to 14 wt %of a plasticizer, such as from 2 wt % to 12 wt %, or from 4 wt % to 10wt % of a plasticizer, where wt % is based on the total weight of thefunctional coating. A functional coating can comprise, for example, lessthan 14 wt % of a plasticizer, less than 12 wt %, less than 12 wt %,less than 8 wt %, less than 6 wt %, or less than 4 wt % of aplasticizer, where wt % is based on the total weight of the functionalcoating. A functional coating can comprise, for example, greater than 0wt % of a plasticizer, greater than 2 wt %, greater than 4 wt %, greaterthan 6 wt %, greater than 8 wt %, greater than 10 wt %, or greater than12 wt % of a plasticizer, where wt % is based on the total weight of thefunctional coating.

A functional coating provided by the present disclosure can comprise,for example, from 60 wt % to 85 wt % of a matrix polymer, from 10 wt %to 20 wt % of an antistatic agent, and from 0 wt % to 14 wt % of aplasticizer, where wt % is based on the total weight of the functionalcoating.

A functional coating provided by the present disclosure can comprise,for example, from 65 wt % to 80 wt % of a matrix polymer, from 12 wt %to 18 wt % of an antistatic agent, and from 2 wt % to 12 wt % of aplasticizer, where wt % is based on the total weight of the functionalcoating.

A functional coating provided by the present disclosure can comprise,for example, from 70 wt % to 80 wt % of a matrix polymer, from 14 wt %to 16 wt % of an antistatic agent, and from 4 wt % to 10 wt % of aplasticizer, where wt % is based on the total weight of the functionalcoating.

A functional coating provided by the present disclosure can comprise,for example, a water-insoluble polymer such as ethylcellulose, awater-soluble polymer such as hydroxypropyl cellulose, an antistaticagent such as talc, and a plasticizer such as dibutyl sebacate.

Pharmaceutical granulations provided by the present disclosure cancomprise a seal coating. Pharmaceutical granulations comprising a sealcoating can be used as immediate release pharmaceutical granulations.

A coated granule provided by the present disclosure can comprise a sealcoat overlying a granule comprising the active pharmaceuticalingredient. A functional coating can overly the seal coat.

A seal coat can minimize the ingress of moisture into the activepharmaceutical ingredient and thereby increase the storage stability ofthe coated granulation by reducing hydrolysis of the activepharmaceutical ingredient. A seal coat can also minimize negativeinteractions between the functional coating and the activepharmaceutical ingredient, and thereby increase the storage stability ofthe coated granulation by reducing hydrolysis of the activepharmaceutical ingredient.

A seal coat can comprise a water-soluble polymer such as, for example,hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylethyl cellulose, polyvinylpyrrolidone, orpolyethylene glycol.

A seal coat can comprise a water-soluble polymer such as hydroxypropylcellulose, hydroxypropylmethyl cellulose or any of the water-solublepolymers disclosed herein.

A seal coat can comprise an antistatic agent such as talc, magnesiumstearate, or a combination thereof.

A seal coat can comprise, for example, hydroxypropyl cellulose,hydroxypropyl cellulose and talc, or hydroxypropylmethyl cellulose andtalc.

A seal coat can comprise, for example, from 65 wt % to 95 wt % of awater soluble polymer, such as from 70 wt % to 90 wt %, or from 75 wt %to 85 wt % of a water soluble polymer; and from 5 wt % to 35 wt % of anantistatic agent, such as from 10 wt % to 30 wt %, or from 15 wt % to 25wt % if an antistatic agent where wt % is based on the total weight ofthe seal coating.

A seal coat can have an average thickness, for example from 0.5 μm to 5μm, from 1 μm to 4 μm, or from 1 μm to 3 μm. A seal coat can have anaverage thickness, for example, less than 5 μm, less than 4 μm, lessthan 3 μm, less than 2 μm, or less than 1 μm.

A seal coat can be applied to a granulation such that the % wg is lessthan 15% wg, less than 10% wg, less than 8% wg, less than 6% wg, or lessthan 4% wg. A seal coat can be applied to a granulation such that the %wg is from 1% wg to 15% wg, from 1% wg to 10% wg, from 2% wg to 8% wg,or from 4% wg to 6% wg.

In certain coated granulations comprising a seal coating comprising awater-soluble polymer, the functional coating does not contain awater-soluble polymer.

A seal coat can be applied to uncoated granules using any suitablemethod such as by spraying a solution, suspension, or dispersion of thefunctional coating onto granules in a fluidized bed apparatus.

A functional coating can be applied to uncoated granules provided by thepresent disclosure or to granules comprising a seal coat by any suitablemethod such as by spraying a solution, suspension, or dispersion of thefunctional coating onto granules in a fluidized bed apparatus.

A controlled release granulation provided by the present disclosure cancomprise granules having a functional coating provided by the presentdisclosure.

A controlled release granulation provided by the present disclosure canbe configured to provide for once a night dosing, once a day dosing(QD), twice a day dosing (BID), three times a day dosing (TID), or fourtimes a day dosing (QID). For example, a controlled release granulationcan release substantially 100% of the active pharmaceutical ingredientover a 24-hour duration, a 12-hour duration, an 8-hour duration, or a4-hour duration.

For example, a controlled release granulation can exhibit a dissolutionprofile as substantially shown, for example, in FIG. 16, 17, 18, or 22.

A controlled release granulation can exhibit a dissolution profile inwhich less than 80% of the active pharmaceutical ingredient is releasedfrom the controlled release granulation within 2 hours, less than 70%,less than 60%, less than 50% or less than 40% is of activepharmaceutical ingredient is released from the controlled releasegranulation within 2 hours, and greater than 80% or greater than 90% ofthe active pharmaceutical ingredient is released from the controlledrelease granulation within 6 hours as determined using a USP Type 2dissolution apparatus in a buffered solution at pH 4.5 at a temperatureof 37° C. and a paddle speed of 75 rpm.

A controlled release granulation can exhibit a dissolution profile inwhich from 35% to 85%, such as from 35% to 80%, from 40% to 75%, or from45% to 70% of the active pharmaceutical ingredient is released from thecontrolled release granulation within 2 hours as determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm.

A controlled release granulation can exhibit a dissolution profile inwhich from 70% to 95%, such as from 70% to 90%, or from 75% to 85% ofthe active pharmaceutical ingredient is released from the controlledrelease granulation within 4 hours as determined using a USP Type 2dissolution apparatus in a buffered solution at pH 4.5 at a temperatureof 37° C. and a paddle speed of 75 rpm.

A controlled release granulation can exhibit a dissolution profile inwhich from 80% to 100%, such as from 85% to 95%, of the activepharmaceutical ingredient is released from the controlled releasegranulation within 6 hours as determined using a USP Type 2 dissolutionapparatus in a buffered solution at pH 4.5 at a temperature of 37° C.and a paddle speed of 75 rpm.

A controlled release granulation can exhibit a dissolution profile inwhich from 35% to 85% of the active pharmaceutical ingredient isreleased from the controlled release granulation within 2 hours, from70% to 95% of the active pharmaceutical ingredient is released from thecontrolled release granulation within 4 hours, and from 80% to 100% ofthe active pharmaceutical ingredient is released from the formulationwithin 6 hours, as determined using a USP Type 2 dissolution apparatusin a buffered solution at pH 4.5 at a temperature of 37° C. and a paddlespeed of 75 rpm.

A controlled release granulation can exhibit a dissolution profile inwhich from 35% to 80% of the active pharmaceutical ingredient isreleased from the controlled release granulation within 2 hours, from70% to 90% of the active pharmaceutical ingredient is released from thecontrolled release granulation within 4 hours, and from 80% to 100% ofthe active pharmaceutical ingredient is released from the formulationwithin 6 hours, as determined using a USP Type 2 dissolution apparatusin a buffered solution at pH 4.5 at a temperature of 37° C. and a paddlespeed of 75 rpm.

A controlled release granulation can exhibit a dissolution profile inwhich from 45% to 70% of the active pharmaceutical ingredient isreleased from the controlled release granulation within 2 hours, from75% to 85% of the active pharmaceutical ingredient is released from thecontrolled release granulation within 4 hours, and from 85% to 95% ofthe active pharmaceutical ingredient is released from the controlledrelease granulation within 6 hours, as determined using a USP Type 2dissolution apparatus in a buffered solution at pH 4.5 at a temperatureof 37° C. and a paddle speed of 75 rpm.

A coated granulation provided by the present disclosure can have a watercontent, for example, less than 2 wt %, less than 1.5 wt % less than 1wt %, less than 0.5 wt %, or less than 0.25 wt %, where wt % is based onthe total weight of the granulation.

A coated granulation provided by the present disclosure can have a watercontent, for example, from 0.1 wt % to 2 wt %, from 0.1 wt % to 1 wt %,or from 0.2 wt % to 0.5 wt %, where wt % is based on the total weight ofthe granulation.

A coated pharmaceutical granulation can have a bulk density, forexample, greater than 0.55 g/mL, greater than 0.60 g/mL, greater than0.65 g/mL, greater than 0.70 g/mL, or greater than 0.75 g/mL.

A coated pharmaceutical granulation can have a bulk density, forexample, from 0.55 g/mL to 0.80 g/mL, from 0.60 g/mL to 0.75 g/mL, from0.60 g/mL to 0.70 g/mL.

Bulk density can be determined using a bulk density cylinder.

A coated pharmaceutical granulation provided by the present disclosurecan be characterized, for example, by a particle size distribution(D50), for example, from 150 μm to 350 μm, such as from 175 μm to 325μm, from 200 μm to 300 μm, or from 225 μm to 275 μm.

A coated pharmaceutical granulation can be characterized, for example,by a particle size distribution (D10) from 50 μm to 150 μm, from 60 μmto 140 μm, from 70 μm, to 120 μm, or from 80 μm to 110 μm.

An uncoated pharmaceutical granulation can be characterized, forexample, by a particle size distribution (D90) from 450 μm to 750 μm,from 475 μm to 725 μm, from 500 μm to 700 μm, from 525 μm to 675 μm, orfrom 550 μm to 650 μm.

A coated pharmaceutical granulation can be characterized, for example,by a particle size distribution (D10) from 50 μm to 150 μm such as from60 μm to 140 μm; a particle size distribution (D50) from 230 μm to 310μm; and a particle size distribution (D90) from 490 μm to 550 μm.

A coated pharmaceutical granulation can be characterized, for example,by a particle size distribution (D10) from 70 μm to 130 μm; a particlesize distribution (D50) from 240 μm to 300 μm; and a particle sizedistribution (D90) from 500 μm to 540 μm.

An example of a particle size distribution for an uncoated granulationprovided by the present disclosure is shown in FIG. 15.

For example, in a coated pharmaceutical granulation 12.9% of the coatedgranules can have a particle size less than 300 μm, 83.8% of the coatedgranules can have a particle size from 300 μm to 600 μm, and 3.3% of thecoated granules can have a particle size from 600 μm to 1190 μm.

A particle size distribution can be determined by laser diffraction orby sieve analysis.

Functional coatings and seal coatings provided by the present disclosurecan be coated onto granulations using any suitable equipment andprocess. Examples of suitable coating methods include Wurster fluid bedfilm coating processes and phase inversion processes.

Examples of coating compositions are provided in the experimentalexamples. A coating composition refers to the composition that isapplied to an uncoated granulation to provide a coated granulation.

A functional coating composition can comprise greater than 70 wt % of analcoholic solvent, greater than 75 wt %, greater than 80 wt %, greaterthan 85 wt %, or greater than 90 wt % of an alcoholic solvent such asethanol, where wt % is based on the total weight of the functionalcoating solution/suspension composition.

A functional coating composition can comprise, for example, less than 20wt % water, less than 15 wt %, less than 10 wt %, or less than 5 wt %water, where wt % is based on the functional coating solution/suspensioncomposition.

For highly water-soluble and hygroscopic active pharmaceuticalingredients it can be useful to minimize the amount of water in thefunctional coating composition. Reducing the level of water in thefunctional coating solution/suspension composition can lead to increasedstatic which can complicate the coating process.

A functional coating solution/suspension composition can comprise, forexample, a solids content less than 20 wt %, less than 18 wt %, lessthan 16 wt %, less than 14 wt %, less than 12 wt %, less than 10 wt %,less than 8 wt %, or less than 6 wt %, where wt % is based on thefunctional coating solution/suspension composition.

A functional coating composition can comprise a solids content from 2 wt% to 20 wt %, from 4 wt % to 16 wt %, from 4 wt % to 12 wt % or from 6wt % to 10 wt %, where wt % is based on the functional coatingcomposition.

A functional coating composition can comprise, for example, from 3 wt %to 10 wt % solids, from 4 wt % to 13 wt % water, from 75 wt % to 90 wt %of an alcoholic solvent such as ethanol, where wt % is based on thetotal weight of the functional coating composition.

Examples of coating process conditions using a Wurster column insertedinto a fluid bed coating equipment are provided in the experimentalexamples.

A granulation provided by the present disclosure can comprise animmediate release granulation.

An immediate release granulation can comprise a plurality of uncoatedgranules. An immediate release granulation comprising a plurality ofuncoated granules can comprise greater than 90 wt % of an activepharmaceutical ingredient provided by the present disclosure such as acompound of Formula (2). An immediate release granulation comprisinguncoated granules can dissolve completely, for example, in less than 10minutes, less than 8 minutes, less than 6 minutes, less than 5 minutes,or less than 4 minutes, when tested in a USP Type 2 dissolutionapparatus in a buffered solution at pH 4.5 at a temperature of 37° C.and a paddle speed of 75 rpm.

An immediate release granulation can comprise a plurality of coatedgranules having an immediate release functional coating. An immediaterelease granulation comprising a plurality of coated granules cancomprise greater than 80 wt % of an active pharmaceutical ingredientprovided by the present disclosure such as a compound of Formula (2). Animmediate release granulation comprising coated granules can dissolvecompletely, for example, in less than 25 minutes, less than 20 minutes,less than 18 minutes, less than 16 minutes, less than 14 minutes, orless than 12 minutes, when tested in a USP Type 2 dissolution apparatusin a buffered solution at pH 4.5 at a temperature of 37° C. and a paddlespeed of 75 rpm. An immediate release granulation comprising coatedgranules can release greater than 80% of the active pharmaceuticalingredient, for example, in less than 10 minutes, less than 8 minutes,less than 6 minutes, or less than 4 minutes, when tested in a USP Type 2dissolution apparatus in a buffered solution at pH 4.5 at a temperatureof 37° C. and a paddle speed of 75 rpm. A coated immediate releasegranulation can comprise a coating comprising a water-soluble polymersuch as, for example, hydroxypropyl cellulose, polyvinyl alcohol,hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose,polyvinylpyrrolidone, or polyethylene glycol. A coated immediate releasegranulation can comprise a coating comprising an antistatic agent suchas talc, magnesium stearate, or silicon dioxide.

A pharmaceutical composition provided by the present disclosure cancomprise a combination of an immediate release granulation and acontrolled release granulation. A pharmaceutical composition cancomprise a weight ratio of a compound of Formula (2) as an immediaterelease granulation to a compound of Formula (2) as a controlled releasegranulation, for example, from 1:1 to 1:4, from 1:1 to 1:3, from 1:1 to1:2 or from 1:2 to 1:3.

A pharmaceutical composition provided by the present disclosure cancomprise a coated granulation provided by the present disclosure.

A pharmaceutical composition can comprise any suitable dosage form fororal administration.

Examples of suitable oral dosage forms include tablets, capsules,caplets, sachets, bottles, stick packs, dispersions, and suspensions.

A pharmaceutical composition provided by the present disclosure cancomprise a suspension for oral administration.

An oral dosage form provided by the present disclosure can comprise, forexample, from 0.1 grams to 20 grams of an active pharmaceuticalingredient, from 0.1 grams to 15 grams, from 0.1 grams to 12 grams, from0.1 grams to 10 grams, from 0.2 grams to 8 grams, from 0.5 grams to 5grams, from 1 gram to 4.5 grams, or from 1.5 grams to 4 grams of anactive pharmaceutical ingredient. An oral dosage form can comprise, forexample, greater than 0.5 grams, greater than 1 gram, greater than 2grams, greater than 3 grams, greater than 4 grams, greater than 6 grams,or greater than 8 grams greater than 10 grams, greater than 14 grams, orgreater than 18 grams of an active pharmaceutical ingredient.

An oral formulation provided by the present disclosure can comprise anoral suspension of coated granules having a controlled releasefunctional coating provided by the present disclosure. An oralformulation can comprise a controlled release granulation provided bythe present disclosure and an immediate release granulation.

An oral formulation can comprise a combination of an immediate releasegranulation and a controlled release granulation provided by the presentdisclosure.

An oral formulation provided by the present disclosure can provide atherapeutically effective amount of an active pharmaceutical ingredientover a period of time.

For example, an oral formulation provided by the present disclosure canprovide a therapeutically effective amount of an active pharmaceuticalingredient over a period of 3 hours, 6 hours, 8 hours, or 10 hours.

An oral formulation provided by the present disclosure can provide atherapeutically effective amount of an active pharmaceutical ingredientover a period from 4 hours to 12 hours, from 4 hours to 10 hours, orfrom 4 hours to 8 hours.

An oral formulation provided by the present disclosure can provide atherapeutically effective amount of an active pharmaceutical ingredientover a duration from 1 hour to 12 hours following oral administration,from 2 hours to 10 hours or from 4 hours to 8 hours following oraladministration.

An oral formulation provided by the present disclosure can be a oncenightly formulation. For a once nightly formulation, a patient canadminister a dose of an active pharmaceutical ingredient before going tobed and sleep through the night such as for 6 hours or for 8 hourswithout having to administer a second dose during the night.

An oral formulation provided by the present disclosure can provide atherapeutically effective amount of a γ-hydroxybutyric acid in theplasma of a patient.

An oral formulation provided by the present disclosure can provide atherapeutically effective amount of γ-hydroxybutyric acid in the plasmaof a patient for a period of 4 hours, 6, hours, 8 hours, or 10 hoursfollowing oral administration of the controlled release oralformulation.

An oral formulation provided by the present disclosure can provide aplasma concentration of γ-hydroxybutyric acid greater than 10 μg/mL formore than 4 hours, more than 6 hours, more than 8 hours, or more than 10hours following oral administration of the controlled release oralformulation.

An oral formulation provided by the present disclosure can provide aplasma concentration of γ-hydroxybutyric acid greater than 15 μg/mL formore than 4 hours, more than 6 hours, more than 8 hours, or more than 10hours following oral administration of the controlled release oralformulation.

An oral formulation provided by the present disclosure can provide atherapeutically effective amount of C_(max) to C_(min) ratio ofγ-hydroxybutyric acid in the plasma of a patient from less than 3 orless than 2 for a duration of 4 hours, 6 hours, 8 hours, or 10 hoursfollowing oral administration of the controlled release oralformulation.

An oral formulation provided by the present disclosure can comprise aγ-hydroxybutyric acid derivative of Formula (2) and can comprise, forexample, 0.5 g-equivalents γ-hydroxybutyric acid, 1 g-equivalents, 2g-equivalents, 3 g-equivalents, 4 g-equivalents, 5 g-equivalents, 6g-equivalents, 7 g-equivalents, 8 g-equivalents, 9 g-equivalents, 10g-equivalents, 11 g-equivalents, or 12 g-equivalents γ-hydroxybutyricacid.

Oral formulations provided by the present disclosure can be provided,for example, as sachets containing a coated granulation provided thepresent disclosure. A sachet can be provided in different doses of theactive pharmaceutical ingredient such as 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g,6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 10 g, 12 g, 15 g, or 20 g of the activepharmaceutical ingredient. The coated granulation can be combined, forexample, with water to provide an orally ingestible dosage form.

γ-Hydroxybutyric acid and γ-hydroxybutyric acid derivatives of Formula(2) can be used to treat narcolepsy, excessive daytime sleepiness,cataplexy, excessive daytime sleepiness associated with narcolepsy,excessive daytime sleepiness associated with Parkinson's disease,excessive daytime sleepiness associated with multiple sclerosis,cataplexy associated with narcolepsy, fatigue, fatigue associated withParkinson's diseases, fatigue associated with multiple sclerosis, andfibromyalgia γ-Hydroxybutyric acid and γ-hydroxybutyric acid derivativesof Formula (2) can be used to treat REM sleep behavior disorder,spasmodic dystonia, schizophrenia, insomnia, insomnia associated withschizophrenia, idiopathic hypersomnia, chronic fatigue syndrome, clusterheadache, Alzheimer's disease, essential tremor, post-traumatic stresssyndrome, insomnia associated with post-traumatic stress syndrome, andanxiety.

Compounds of Formula (2) are prodrugs of γ-hydroxybutyric acid thatfollowing oral administration provide an oral bioavailability ofγ-hydroxybutyric acid in the systemic circulation of a patient.

The effectiveness of the treatment can be measured by one or more of thefollowing criteria: increase in the mean sleep latency such asdetermined the Maintenance of Wakefulness Test (MWT); improvement in theClinical Global Impression (CGI) rating of sleepiness; decrease in thenumber of cataplexy attacks (NCA) such as determined from the cataplexyfrequency item in the Sleep and Symptoms Daily Diary; decrease indisturbed nocturnal sleep (DNS), the disturbed nocturnal events or theadverse respiratory events such as determined by polysomnographic (PSG)measures of sleep fragmentation; decrease in excessive daytimesleepiness (EDS) such as measured by patient report via the EpworthSleepiness Scale (ESS); decrease in daytime sleepiness as measured bythe Maintenance of Wakefulness Test based on EEG measures ofwakefulness; decrease PSG transitions from N/2 to N/3 and REM sleep towake and Ni sleep such a determined as described in the AASM Manual forthe Scoring of Sleep and Associated Events; decrease in the number ofarousals or wakenings such as determined from a PSG as defined by theAmerican Academy of Sleep Medicine; improvement in sleep quality such asdetermined using (i) the Sleep and Symptom Daily Diary, (ii) VisualAnalog Scale (VAS) for sleep quality and sleep diary, and/or (iii) VASfor the refreshing nature of sleep; and decrease in the HypnagogicHallucinations (HH) or sleep paralysis (SP) symptoms in NT1 narcolepsypatients such as measured by the Sleep and Symptom Daily Diary.

Compounds of Formula (2) and pharmaceutical compositions thereof can beused to treat a disease known to be or determined to be treated byγ-hydroxybutyric acid.

Compounds of Formula (2) and pharmaceutical compositions thereof can beused to treat a disease known to be or determined to be treated byγ-hydroxybutyric acid and one or more additional therapeutic agents.

Compounds of Formula (2) and pharmaceutical composition can be used totreat excessive daytime sleepiness associated with narcolepsy, excessivedaytime sleepiness associated with Parkinson's disease, excessivedaytime sleepiness associated with multiple sclerosis, cataplexyassociated with narcolepsy, fatigue in a patient with Parkinson'sdisease, fatigue in a patient with multiple sclerosis, or fibromyalgia.

Methods provided by the present disclosure include providing atherapeutically effective amount of γ-hydroxybutyric acid in thesystemic circulation of a patient comprising administering to a patienta compound of Formula (2) or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof.

A pharmaceutical composition provided by the present disclosure mayfurther comprise one or more active pharmaceutical compounds in additionto a compound of Formula (2). Such compounds may be provided to treatthe disease being treated with the compound of Formula (2) or to treat adisease, disorder, or condition other than that being treated with thecompound of Formula (2).

A compound of Formula (2) or a pharmaceutical composition thereof may beused in combination with at least one other therapeutic agent. Acompound of Formula (2) or a pharmaceutical composition thereof may beadministered to a patient together with another compound for treating abacterial infection in the patient. The at least one other therapeuticagent may be a different compound encompassed by Formula (2). A compoundof Formula (2) and the at least one other therapeutic agent may actadditively or synergistically. The at least one additional therapeuticagent may be included in the same pharmaceutical composition or vehiclecomprising the compound of Formula (2) or may be in a separatepharmaceutical composition or vehicle. Accordingly, methods provided bythe present disclosure further include, in addition to administering acompound of Formula (2), administering one or more therapeutic agentseffective for treating a different disease, disorder or condition otherthan the disease being treated with γ-hydroxybutyric acid. Methodsprovided by the present disclosure include administration of a compoundof Formula (2) or a pharmaceutical composition thereof and one or moreother therapeutic agents provided that the combined administration doesnot inhibit the therapeutic efficacy of a compound of Formula (2) and/orγ-hydroxybutyric acid and/or does not produce adverse combinationeffects.

A pharmaceutical composition comprising a compound of Formula (2) may beadministered concurrently with the administration of another therapeuticagent, which may be part of the same pharmaceutical composition as, orin a different pharmaceutical composition than that comprising acompound of Formula (2). A compound of Formula (2) or a pharmaceuticalcomposition thereof may be administered prior or subsequent toadministration of another therapeutic agent. In certain embodiments ofcombination therapy, the combination therapy may comprise alternatingbetween administering a compound of Formula (2) and a pharmaceuticalcomposition comprising another therapeutic agent such as to minimizeadverse drug effects associated with a particular drug. When a compoundof Formula (2) is administered concurrently with another therapeuticagent that potentially may produce an adverse drug effect including, forexample, toxicity, the other therapeutic agent may be administered at adose that falls below the threshold at which the adverse drug reactionis elicited.

A pharmaceutical composition comprising a compound of Formula (2) may beadministered with one or more substances, for example, to enhance,modulate and/or control release, bioavailability, therapeutic efficacy,therapeutic potency, and/or stability of a compound of Formula (2). Forexample, to enhance the therapeutic efficacy of a compound of Formula(2), a compound of Formula (2) or a pharmaceutical compositioncomprising a compound of Formula (2) may be co-administered with one ormore active agents to increase the absorption or diffusion and/ortransport of the compound of Formula (2) from the gastrointestinal tractinto the systemic circulation, or to inhibit degradation of the compoundof Formula (2) in the blood of a patient. A pharmaceutical compositioncomprising a compound of Formula (2) may be co-administered with anactive agent having pharmacological effects that enhance the therapeuticefficacy of the compound of Formula (2) or γ-hydroxybutyric acid.

ASPECTS OF THE INVENTION

The invention is further defined by the following aspects.

Aspect 1. A pharmaceutical granulation comprising a plurality of coatedgranules comprising a core and a functional coating surrounding thecore, wherein, the pharmaceutical granulation is characterized by aparticle size distribution (PSD) (D50) from 150 μm to 400 μm, whereinparticle size distribution is determined by sieve analysis; and the corecomprises greater than 90 wt % of an active pharmaceutical ingredient,wherein wt % is based on the total weight of the core.

Aspect 2. The pharmaceutical granulation of aspect 1, wherein thepharmaceutical granulation comprises from 60 wt % to 85 wt % of theactive pharmaceutical ingredient, where wt % is based on the totalweight of the pharmaceutical granulation.

Aspect 3. The pharmaceutical granulation of any one of aspects 1 to 2,wherein the functional coating comprises a controlled release coating.

Aspect 4. The pharmaceutical granulation of any one of aspects 1 to 3,wherein the functional coating comprises from 60 wt % to 85 wt % of amatrix polymer, wherein wt % is based on the total weight of thefunctional coating.

Aspect 5. The pharmaceutical granulation of aspect 4, wherein the matrixpolymer comprises a water-insoluble polymer.

Aspect 6. The pharmaceutical granulation of aspect 5, wherein thewater-insoluble polymer comprises ethylcellulose.

Aspect 7. The pharmaceutical granulation of any one of aspects 1 to 6,wherein the functional coating comprises from 0 wt % to 10 wt % of apore forming polymer, wherein wt % is based on the total weight of thepolymers.

Aspect 8. The pharmaceutical granulation of aspect 7, wherein the poreforming polymer comprises a water-soluble polymer.

Aspect 9. The pharmaceutical granulation of aspect 8, wherein thewater-soluble polymer comprises hydroxypropyl cellulose.

Aspect 10. The pharmaceutical granulation of any one of aspects 1 to 9,wherein the functional coating comprises from 0 wt % to 14 wt % of aplasticizer, wherein wt % is based on the total weight of the functionalcoating.

Aspect 11. The pharmaceutical granulation of aspect 10, wherein theplasticizer comprises dibutyl sebacate.

Aspect 12. The pharmaceutical granulation of any one of aspects 1 to 11,wherein the functional coating comprises from 10 wt % to 20 wt % anantistatic agent, wherein wt % is based on the total weight of thefunctional coating.

Aspect 13. The pharmaceutical granulation of aspect 12, wherein theantistatic agent comprises talc.

Aspect 14. The pharmaceutical granulation of any one of aspects 12 to13, wherein the functional coating comprises: from 60 wt % to 85 wt % ofa matrix polymer; from 10 wt % to 20 wt % of an antistatic agent; andfrom 0 wt % to 14 wt % of a plasticizer, wherein wt % is based on thetotal weight of the functional coating.

Aspect 15. The pharmaceutical granulation of any one of aspects 1 to 14,wherein, the core represents from 65 wt % to 85 wt % of the total weightof the coated granules; and the functional coating represents from 15 wt% to 35 wt % of the total weight of the coated granules.

Aspect 16. The pharmaceutical granulation of any one of aspects 1 to 15,wherein the functional coating has a thickness from 5 μm to 20 μm.

Aspect 17. The pharmaceutical granulation of any one of aspects 1 to 16,wherein the pharmaceutical granulation has a water content less than 1wt %, wherein wt % is based on the total weight of the pharmaceuticalgranulation.

Aspect 18. The pharmaceutical granulation of any one of aspects 1 to 17,further comprising a seal coating surrounding the core, and wherein thefunctional coating surrounds the seal coating.

Aspect 19. The pharmaceutical granulation of aspect 18, wherein the sealcoating comprises hydroxypropyl cellulose.

Aspect 20. The pharmaceutical granulation of any one of aspects 18 to19, wherein the granules comprise from 2 wt % to 15 wt % of the sealcoating.

Aspect 21. The pharmaceutical granulation of any one of aspects 1 to 20,wherein from 35% to 80% of the active pharmaceutical ingredient isreleased from the formulation within 2 hours when tested in a USP Type 2dissolution apparatus in a buffered solution at pH 4.5 at a temperatureof 37° C. and a paddle speed of 75 rpm.

Aspect 22. The pharmaceutical granulation of any one of aspects 1 to 20,wherein from 70% to 90% of the active pharmaceutical ingredient isreleased from the formulation within 4 hours when tested in a USP Type 2dissolution apparatus in a buffered solution at pH 4.5 at a temperatureof 37° C. and a paddle speed of 75 rpm.

Aspect 23. The pharmaceutical granulation of any one of aspects 1 to 20,wherein from 80% to 100% of the active pharmaceutical ingredient isreleased from the formulation within 6 hours when tested in a USP Type 2dissolution apparatus in a buffered solution at pH 4.5 at a temperatureof 37° C. and a paddle speed of 75 rpm.

Aspect 24. The pharmaceutical granulation of any one of aspects 1 to 23,wherein the active pharmaceutical ingredient has an aqueous solubilitygreater than 100 mg/mL.

Aspect 25. The pharmaceutical granulation of any one of aspects 1 to 23,wherein the active pharmaceutical ingredient has an aqueous solubilityfrom 100 mg/mL to 1,000 mg/mL.

Aspect 26. The pharmaceutical granulation of any one of aspects 1 to 25,wherein the active pharmaceutical ingredient comprises γ-hydroxybutyricacid or a pharmaceutically acceptable salt thereof.

Aspect 27. The pharmaceutical granulation of any one of aspects 1 to 26,wherein the active pharmaceutical ingredient comprises a derivative ofγ-hydroxybutyric acid or a pharmaceutically acceptable salt thereof.

Aspect 28. The pharmaceutical granulation of any one of aspects 1 to 27,wherein the active pharmaceutical ingredient comprises a compound ofFormula (2):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   R¹ is selected from hydrogen and C₁₋₆ alkyl; and    -   each of R² and R³ is independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ alkoxycarbonyl, and C₃₋₆ cycloalkoxycarbonyl.

Aspect 29. The pharmaceutical granulation of aspect 28, wherein theactive pharmaceutical ingredient is selected from:

-   4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(glycyloxy)butanoic acid;-   4-((D-valyl)oxy)butanoic acid;-   4-((L-alanyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid;-   4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid;-   4-((L-valyl)oxy)butanoic acid;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 30. The pharmaceutical granulation of aspect 28, wherein theactive pharmaceutical ingredient comprises 4-((L-valyl)oxy)butanoic acid(2a) or a pharmaceutically acceptable salt thereof:

Aspect 31. A pharmaceutical composition comprising the pharmaceuticalgranulation of any one of aspects 1 to 30.

Aspect 32. The pharmaceutical composition of aspect 31, wherein thepharmaceutical composition is an oral formulation.

Aspect 33. The pharmaceutical composition of any one of aspects 31 to32, wherein the pharmaceutical composition is a controlled releaseformulation.

Aspect 34. The pharmaceutical composition of any one of aspects 31 to33, wherein the pharmaceutical composition comprises:

a controlled release portion, wherein the controlled release portioncomprises the pharmaceutical granulation of claim 1; and

the pharmaceutical composition n further comprises an immediate releaseportion, an extended release portion, or a combination thereof.

Aspect 35. The pharmaceutical composition of any one of aspects 31 to34, wherein the pharmaceutical composition is a BID formulation.

Aspect 36. The pharmaceutical composition of any one of aspects 31 to34, wherein the pharmaceutical composition is a QD formulation.

Aspect 37. The pharmaceutical composition of any one of aspects 31 to36, wherein the pharmaceutical composition comprises from 500 mgequivalents to 12 g equivalents of γ-hydroxybutyric acid or apharmaceutically acceptable salt thereof.

Aspect 38. The pharmaceutical composition of any one of aspects 31 to37, wherein the active pharmaceutical ingredient comprisesγ-hydroxybutyric acid or a pharmaceutically acceptable salt thereof, aderivative of γ-hydroxybutyric acid or a pharmaceutically acceptablesalt thereof, a compound of Formula (2) or a pharmaceutically acceptablesalt thereof, or a combination of any of the foregoing.

Aspect 39. The pharmaceutical composition of aspect 38, wherein theactive pharmaceutical ingredient is selected from:

-   4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(glycyloxy)butanoic acid;-   4-((D-valyl)oxy)butanoic acid;-   4-((L-alanyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid;-   4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid;-   4-((L-valyl)oxy)butanoic acid;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 40. The pharmaceutical composition of any one of aspects 38 to39, wherein the pharmaceutical composition comprises a therapeuticallyeffective amount of the active pharmaceutical ingredient for treatingexcessive daytime sleepiness associated with narcolepsy, excessivedaytime sleepiness associated with Parkinson's disease, excessivedaytime sleepiness associated with multiple sclerosis, cataplexyassociated with narcolepsy, fatigue in a patient with Parkinson'sdisease, fatigue in a patient with multiple sclerosis, or fibromyalgia.

Aspect 41. A method of providing a therapeutically effective amount ofγ-hydroxybutyric acid in the systemic circulation of a patent comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the pharmaceutical composition of any one of aspects 38 to 39for treating a disease.

Aspect 42. A method of treating a disease in a patient, wherein thedisease is known to be treated by administering γ-hydroxybutyric acid,comprising administering to a patient in need thereof a therapeuticallyeffective amount of the pharmaceutical composition of any one of aspects38 to 39.

Aspect 43. A method of treating a disease in a patient, wherein thedisease is known to be treated by administering γ-hydroxybutyric acid,comprising administering to a patient in need thereof, a therapeuticallyeffective amount of the pharmaceutical composition of any one of aspects38 to 39.

Aspect 44. The method of any one of aspects 41 to 43, wherein, followingadministration to the patient, the pharmaceutical composition provides atherapeutically effective amount of γ-hydroxybutyric acid in thesystemic circulation of the patient for treating the disease.

Aspect 45. The method of any one of aspects 41 to 44, whereinadministering comprises orally administering.

Aspect 46. The method of any one of aspects 41 to 45, wherein thedisease is selected from excessive daytime sleepiness associated withnarcolepsy, excessive daytime sleepiness associated with Parkinson'sdisease, excessive daytime sleepiness associated with multiplesclerosis, cataplexy associated with narcolepsy, fatigue in a patientwith Parkinson's disease, fatigue in a patient with multiple sclerosis,and fibromyalgia.

Aspect 47. A method of coating a granulation comprising applying acoating formulation to a pharmaceutical granulation comprising aplurality of granules comprising an active pharmaceutical ingredient,wherein the coating formulation comprises from 4 wt % to 12 wt % solids;from 3 wt % to 7 wt % water; and from 82 wt % to 92 wt % ethanol.

Aspect 48. The method of aspect 47, wherein applying comprises spraying.

Aspect 49. The method of any one of aspects 47 to 48, the granulescomprise an active pharmaceutical ingredient having an aqueoussolubility greater than 100 mg/mL.

Aspect 1A. A pharmaceutical granulation comprising a plurality of coatedgranules, wherein, the coated granules comprise a core and a functionalcoating surrounding the core; the core comprises greater than 85 wt % ofan active pharmaceutical ingredient, wherein the active pharmaceuticalingredient has an aqueous solubility greater than 100 mg/mL; and wt % isbased on the total weight of the core; and the functional coatingcomprises a plasticizer.

Aspect 2A. The pharmaceutical granulation of aspect 1A, wherein thepharmaceutical granulation comprises from 50 wt % to 90 wt % of theactive pharmaceutical ingredient, wherein wt % is based on the totalweight of the pharmaceutical granulation.

Aspect 3A. The pharmaceutical granulation of any one of aspects 1A to2A, wherein the functional coating comprises a controlled releasecoating.

Aspect 4A. The pharmaceutical granulation of any one of aspects 1A to3A, wherein the functional coating comprises from 60 wt % to 85 wt % ofa matrix polymer, wherein wt % is based on the total weight of thefunctional coating.

Aspect 5A. The pharmaceutical granulation of aspect 4A, wherein thematrix polymer comprises a water-insoluble polymer.

Aspect 6A. The pharmaceutical granulation of aspect 5A, wherein thewater-insoluble polymer comprises ethylcellulose.

Aspect 7A. The pharmaceutical granulation of any one of aspects 1A to6A, wherein the functional coating comprises from 0.5 wt % to 20 wt % ofa water-soluble polymer, wherein wt % is based on the total weight ofthe matrix polymer.

Aspect 8A. The pharmaceutical granulation of aspect 7A, wherein thewater-soluble polymer comprises hydroxypropyl cellulose.

Aspect 9A. The pharmaceutical granulation of any one of aspects 4A to8A, wherein the matrix polymer comprises from 92 wt % to 98 wt % of awater-insoluble polymer and from 2 wt % to 8 wt % of a water-solublepolymer, wherein wt % is based on the total weight of the matrixpolymer.

Aspect 10A. The pharmaceutical granulation of any one of aspects 1A to9A, wherein the functional coating comprises from 3 wt % to 13 wt % ofthe plasticizer, wherein wt % is based on the total weight of thefunctional coating.

Aspect 11A. The pharmaceutical granulation of aspect 10A, wherein theplasticizer comprises dibutyl sebacate.

Aspect 12A. The pharmaceutical granulation of any one of aspects 1A to11A, wherein the functional coating comprises from 10 wt % to 20 wt % anantistatic agent, wherein wt % is based on the total weight of thefunctional coating.

Aspect 13A. The pharmaceutical granulation of aspect 12A, wherein theantistatic agent comprises talc.

Aspect 14A. The pharmaceutical granulation of any one of aspects 1A to13A, wherein the functional coating comprises from 60 wt % to 85 wt % ofa matrix polymer; from 10 wt % to 20 wt % of an antistatic agent; andfrom 3 wt % to 13 wt % of the plasticizer, wherein wt % is based on thetotal weight of the functional coating.

Aspect 15A. The pharmaceutical granulation of any one of aspects 1A to14A, wherein the coated granules comprise: from 55 wt % to 90 wt % ofthe core; and from 10 wt % to 45 wt % of the functional coating, whereinwt % is based on the total weight of the coated granules.

Aspect 16A. The pharmaceutical granulation of any one of aspects 1A to15A, wherein the functional coating has a thickness from 5 μm to 30 μm.

Aspect 17A. The pharmaceutical granulation of any one of aspects 1A to16A, wherein the pharmaceutical granulation has a water content lessthan 1 wt %, wherein wt % is based on the total weight of thepharmaceutical granulation.

Aspect 18A. The pharmaceutical granulation of any one of aspects 1A to17A, wherein, the coated granules comprise a seal coating surroundingthe core; and the functional coating surrounds the seal coating.

Aspect 19A. The pharmaceutical granulation of aspect 18A, wherein theseal coating comprises hydroxypropyl cellulose.

Aspect 20A. The pharmaceutical granulation of any one of aspects 18A to19A, wherein the coated granules comprise from 2 wt % to 15 wt % of theseal coating, wherein wt % is based on the total weight of the granules.

Aspect 21A. The pharmaceutical granulation of any one of aspects 18A to20A, wherein the seal coating has a thickness from 0.5 μm to 5 μm.

Aspect 22A. The pharmaceutical granulation of any one of aspects 1A to21A, wherein the active pharmaceutical ingredient has an aqueoussolubility greater than 100 mg/mL.

Aspect 23A. The pharmaceutical granulation of any one of aspects 1A to21A, wherein the active pharmaceutical ingredient has an aqueoussolubility from 100 mg/mL to 1,000 mg/mL.

Aspect 24A. The pharmaceutical granulation of any one of aspects 1A to23A, wherein the active pharmaceutical ingredient comprisesγ-hydroxybutyric acid or a pharmaceutically acceptable salt thereof.

Aspect 25A. The pharmaceutical granulation of any one of aspects 1A to23A, wherein the active pharmaceutical ingredient comprises a derivativeof γ-hydroxybutyric acid or a pharmaceutically acceptable salt thereof.

Aspect 26A. The pharmaceutical granulation of any one of aspects 1A to23A, wherein the active pharmaceutical ingredient comprises a compoundof Formula (2):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   R¹ is selected from hydrogen and C₁₋₆ alkyl; and    -   each of R² and R³ is independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ alkoxycarbonyl, and C₃₋₆ cycloalkoxycarbonyl.

Aspect 27A. The pharmaceutical granulation of any one of aspects 1A to23A, wherein the active pharmaceutical ingredient is selected from:

-   4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(glycyloxy)butanoic acid;-   4-((D-valyl)oxy)butanoic acid;-   4-((L-alanyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid;-   4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid;-   4-((L-valyl)oxy)butanoic acid;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 28A. The pharmaceutical granulation of any one of aspects 1A to23A, wherein the active pharmaceutical ingredient comprises4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable saltthereof:

Aspect 29A. The pharmaceutical granulation of any one of aspects 1A to28A, wherein the coated granules are characterized by a particle sizedistribution (PSD) (D50) from 150 μm to 500 μm, wherein the particlesize distribution is determined by laser diffraction.

Aspect 30A. The pharmaceutical granulation of any one of aspects 1A to29A, wherein from 35% to 85% of the active pharmaceutical ingredient isreleased from the pharmaceutical granulation within 2 hours when testedin a USP Type 2 dissolution apparatus in a buffered solution at pH 4.5at a temperature of 37° C. and a paddle speed of 75 rpm.

Aspect 31A. The pharmaceutical granulation of any one of aspects 1A to30A, wherein from 70% to 95% of the active pharmaceutical ingredient isreleased from the pharmaceutical granulation within 4 hours when testedin a USP Type 2 dissolution apparatus in a buffered solution at pH 4.5at a temperature of 37° C. and a paddle speed of 75 rpm.

Aspect 32A. The pharmaceutical granulation of any one of aspects 1A to31A, wherein from 80% to 100% of the active pharmaceutical ingredient isreleased from the pharmaceutical granulation within 6 hours when testedin a USP Type 2 dissolution apparatus in a buffered solution at pH 4.5at a temperature of 37° C. and a paddle speed of 75 rpm.

Aspect 33A. A pharmaceutical composition comprising the pharmaceuticalgranulation of any one of aspects 1A to 32A.

Aspect 34A. The pharmaceutical composition of aspect 33A, wherein thepharmaceutical composition is an oral formulation.

Aspect 35A. The pharmaceutical composition of aspect 34A, wherein theoral formulation comprises an oral suspension.

Aspect 36A. The pharmaceutical composition of any one of aspects 31A to35A, wherein the pharmaceutical composition comprises: a controlledrelease portion, wherein the controlled release portion comprises thepharmaceutical granulation; and an immediate release portion, anextended release portion, or a combination thereof.

Aspect 37A. The pharmaceutical composition of any one of aspects 3A1 to36A, wherein the immediate release portion comprises immediate releasegranules, wherein, the immediate release granules comprise a sealcoating surrounding a core; and the core comprises greater than 85 wt %of the active pharmaceutical ingredient.

Aspect 38A. The pharmaceutical composition of any one of aspects 31A to37A, wherein the pharmaceutical composition is a BID formulation.

Aspect 39A. The pharmaceutical composition of any one of aspects 31A to38A, wherein the pharmaceutical composition is a QD formulation.

Aspect 40A. The pharmaceutical composition of any one of aspects 31A to39A, wherein the pharmaceutical composition comprises from 500 mgequivalents to 12 g equivalents of γ-hydroxybutyric acid.

Aspect 41A. The pharmaceutical composition of any one of aspects 31A to39A, wherein the active pharmaceutical ingredient comprisesγ-hydroxybutyric acid or a pharmaceutically acceptable salt thereof, aderivative of γ-hydroxybutyric acid or a pharmaceutically acceptablesalt thereof, a compound of Formula (2) or a pharmaceutically acceptablesalt thereof, or a combination of any of the foregoing.

Aspect 42A. The pharmaceutical composition of any one of aspects 31A to39A, wherein the active pharmaceutical ingredient comprises:

-   4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(glycyloxy)butanoic acid;-   4-((D-valyl)oxy)butanoic acid;-   4-((L-alanyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid;-   4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid;-   4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid;-   4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid;-   4-((L-valyl)oxy)butanoic acid;

a pharmaceutically acceptable salt of any of the foregoing; or

a combination of any of the foregoing.

Aspect 43A. The pharmaceutical composition of any one of aspects 31A to39A, wherein the active pharmaceutical ingredient comprises4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable saltthereof:

Aspect 44A. The pharmaceutical composition of any one of aspects 40A to42A, wherein the pharmaceutical composition comprises a therapeuticallyeffective amount of the active pharmaceutical ingredient for treatingexcessive daytime sleepiness associated with narcolepsy, excessivedaytime sleepiness associated with Parkinson's disease, excessivedaytime sleepiness associated with multiple sclerosis, cataplexyassociated with narcolepsy, fatigue in a patient with Parkinson'sdisease, fatigue in a patient with multiple sclerosis, or fibromyalgia.

Aspect 45A. A method of providing a therapeutically effective amount ofγ-hydroxybutyric acid in the systemic circulation of a patent fortreating a disease comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the pharmaceuticalcomposition of any one of aspects 40A to 43A for treating the disease.

Aspect 46A. A method of treating a disease in a patient, wherein thedisease is known to be treated by administering γ-hydroxybutyric acid,comprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical composition ofany one of aspects 40 to 43A for treating the disease.

Aspect 47A. The method of any one of aspect 45A to 46A, wherein,following administration to the patient, the pharmaceutical compositionprovides a therapeutically effective amount of γ-hydroxybutyric acid inthe systemic circulation of the patient for treating the disease.

Aspect 48A. The method of any one of aspects 45A to 47A, whereinadministering comprises orally administering.

Aspect 49A. The method of any one of aspects 45A to 48A, wherein thedisease is selected from excessive daytime sleepiness associated withnarcolepsy, excessive daytime sleepiness associated with Parkinson'sdisease, excessive daytime sleepiness associated with multiplesclerosis, cataplexy associated with narcolepsy, fatigue in a patientwith Parkinson's disease, fatigue in a patient with multiple sclerosis,and fibromyalgia.

Aspect 50A. A method of coating a pharmaceutical granulation comprisingapplying a coating composition to a pharmaceutical granulationcomprising a plurality of granules, wherein the coating compositioncomprises: rom 4 wt % to 12 wt % solids; greater than 10 wt % water; andfrom 75 wt % to 92 wt % ethanol; wherein wt % is based on the totalweight of the coating composition; and the granules comprise: a corecomprising no less than 90 wt % of an active pharmaceutical ingredient;and the active pharmaceutical ingredient has an aqueous solubilitygreater than 100 mg/mL, wherein wt % is based on the total weight of thecore.

Aspect 51A. The method of aspect 50A, wherein the solids comprise from 3wt % to 13 wt % of a plasticizer, wherein wt % is based on the totalweight of the solids.

Aspect 5A1. The method of any one of aspects 49A to 50A, wherein, rom 60wt % to 85 wt % of a matrix polymer; and from 10 wt % to 20 wt % of anantistatic agent, herein wt % is based on the total weight of thesolids.

Aspect 52A. The method of any one of aspects 49A to 51A, wherein thegranules comprise a seal coating surrounding the core.

Aspect 53A. The method of any one of aspects 49A to 52A, whereinapplying comprises spraying.

Aspect 54A. The method of any one of aspects 49A to 53A, wherein themethod comprises drying the applied coating composition.

EXAMPLES

Embodiments provided by the present disclosure are further illustratedby reference to the following examples, which describe uncoatedpharmaceutical granulations, uncoated pharmaceutical granules, coatedpharmaceutical granulations, coated pharmaceutical granules, oralcontrolled release pharmaceutical compositions and methods of making thecoated pharmaceutical granulations and granules provided by the presentdisclosure. It will be apparent to those skilled in the art that manymodifications, both to materials, and methods, may be practiced withoutdeparting from the scope of the disclosure.

Example 1 Granulation of Active Pharmaceutical Ingredient

Granulations of an active pharmaceutical ingredient were prepared asdescribed in Examples 7-9 of U.S. application Ser. No. 17/350,478.

An active pharmaceutical ingredient used to prepare the pharmaceuticalgranulations was the compound of Formula (2a), 4-((L-valyl)oxy)butanoicacid, and had a purity of 99.3%.

An active pharmaceutical ingredient having a bulk density of 0.263 g/mLwas passed through a Comil® fitted with a 0.056-inch screen. Prior toco-milling the active pharmaceutical ingredient was stored in a dryenvironment.

The constituents of the dry mixture in terms of wt % were 98.5 wt %active pharmaceutical ingredient, 0.5 wt % binder, and 1 wt % antistaticagent.

Distilled water (4.7 wt %) was added to the dry mixture using a pump anda 2-fluid spray nozzle with atomizing air set to 4 psi.

The granulation was retained in a jacketed 4-liter bowl throughoutprocessing.

The wet granulation was granulated for 9.7 minutes at a mixer speed of850 rpm and a chopper speed of 3,600 rpm.

The wet granulation was wet massed for up to 60 minutes at a mixer speedof 547 rpm and a chopper speed of 1,800 rpm, while the temperature ofthe wet granulation was maintained between 23.1° C. and 23.6° C. Duringwet massing a chiller was attached to the bowel to maintain thetemperature less than 25° C.

The granulation was characterized by a granule bulk density from 0.68g/mL to 0.714 g/mL and a friability of about 1.02%.

Uncoated pharmaceutical granulations having a granule diameter from 200μm to 425 μm were used to prepare the coated pharmaceutical granulationsdescribed in the Examples.

Example 2

Coated Granulation (2)

The constituents of the functional coating formulation are provided inTable 1.

TABLE 1 Functional coating formulation. Component Total (wt %) Solids(wt %) Eudragit® RS 100 5.62 56.25 ethylacrylate/methylmethacrylatecopolymer Eudragit® RL 100 0.62 6.25 ethylacrylate/methylmethacrylatecopolymer Triethyl citrate 0.63 6.25 Talc 3.13 31.25 Water 4.5 —Ethanol, 100% 85.5 —

The granulation was coated with the functional coating described inTable 1 using a Wurster column inserted in fluid bed. The coatingconditions are provided in FIG. 21. The functional coating was appliedto achieve a 10% wg or 20% wg.

The dissolution profile of the granulation was determined using a USPType 2 dissolution apparatus a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 1. The designations 20% wg (1) and 20% wg (2)refer to two separate experiments using a granulation having a 20% wgcoating.

Example 3 Coated Granulation (3)

A granulation containing granules having 98.5 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by agranule diameter from 200 μm to 425 μm was used.

The constituents of the functional coating formulation are provided inTable 2.

TABLE 2 Functional coating formulation. Component Total (wt %) Solids(wt %) Aqualon® EC N10 5.54 69.16 ethylcellulose Klucel® HPC EF 0.627.74 Hydroxypropyl cellulose Dibutyl Sebacate 0.62 7.74 Talc 1.23 15.36Water 4.60 — Ethanol, 95% 87.40 —

The granulation was coated with the functional coating described inTable 2 using a Wurster column inserted in fluid bed. The coatingconditions are provided in FIG. 21. The functional coating was appliedto achieve a 10% wg or 20% wg. Static build up increased during thecoating process and agglomerates began to form at about a 10% wg.

The dissolution profile of the granulation was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 2. The designations 20% wg (1) and 20% wg (2)refer to two separate experiments using a granulation having a 20% wgcoating.

Example 4 Coated Granulation (4)

A granulation containing granules having 98.5 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by agranule diameter from 200 μm to 425 μm was used.

The constituents of the functional coating formulation are provided inTable 3.

TABLE 3 Functional coating formulation. Component Total (wt %) Solids(wt %) Eudragit® RS 100 4.4 62.50 ethylacrylate/methylmethacrylatecopolymer Eudragit® RL 100 — — ethylacrylate/methylmethacrylatecopolymer Dibutyl Sebacate 0.4 6.25 Talc 2.2 31.25 Ethanol, 95% 93.0 —

The granulation was coated with the functional coating described inTable 3 using a Wurster column insert in a fluid bed. The coatingconditions are provided in FIG. 21. The functional coating was appliedto achieve a granulation having a 20% wg. Static build up increasedduring the coating process.

The dissolution profile of the granulation was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 3. The designations 30% wg (1) and 30% wg (2)refer to two separate experiments using a granulation having a 30% wgcoating.

Example 5 Coated Granulation (5)

A granulation containing granules having 98.5 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by agranule diameter from 200 μm to 425 μm was used.

The constituents of the functional coating formulation are provided inTable 4.

TABLE 4 Functional coating formulation. Component Total (wt %) Solids(wt %) Aquaion® EC N10 5.43 67.86 ethylcellulose Klucel® HPC EF 0.293.57 Hydroxypropyl cellulose Dibutyl sebacate 0.57 7.14 Talc 1.71 21.43Water 4.60 — Ethanol, 95% 87.40 —

In this coating formulation the ratio of ethylcellulose (insoluble) tohydroxypropyl cellulose (soluble) was increased to 95:5 wt/wt to extendthe release time without increasing the % wg. The talc content was alsoincreased from 20 wt % to 30 wt % of the weight of the polymers toreduce static buildup.

The granulation was coated with the functional coating described inTable 4 using a Wurster column insert in a fluid bed. The coatingconditions are provided in FIG. 21. The functional coating was appliedto achieve a granulation having a 20% wg and 30% wg.

The dissolution profile of the granulation was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 4. The designations 30% wg (1) and 30% wg (2)refer to two separate experiments using a granulation having a 30% wgcoating.

The dissolution profiles of the granulations having anethylcellulose/hydroxypropyl cellulose (EC/HPC) functional coatings ofExamples 2 and 4 are compared in FIG. 5.

Example 6 Coated Granulation (6)

A granulation containing granules having 98.5 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by agranule diameter from 200 μm to 425 μm was used.

The constituents of the functional coating formulation are provided inTable 5.

TABLE 5 Functional coating formulation. Component Total (wt %) Solids(wt %) Aquaion® EC N10 5.85 73.08 ethylcellulose Klucel® HPC EF 0.313.85 Hydroxypropyl cellulose Dibutyl sebacate 0.62 7.69 Talc 1.23 15.38Water 6.78 — Ethanol, 95% 85.22 —

In this coating formulation the talc content was set to 20% that of thepolymers and the water content was increased to 12 wt % of the solvent.

The granulation was coated with the functional coating described inTable 5 using a Wurster column insert in a fluid bed. The coatingconditions are provided in FIG. 21. The functional coating was appliedto achieve a granulation having a 20% wg, 25% wg, and 35% wg.Significant agglomeration was evident.

The dissolution profile of the granulation was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 6.

Example 7 Coated Granulation (7)

A granulation containing granules having 98.5 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by agranule diameter from 200 μm to 425 μm was used.

The constituents of the functional coating formulation are provided inTable 6.

TABLE 6 Functional coating formulation. Component Total (wt %) Solids(wt %) Aquaion® EC N10 5.85 73.08 ethylcellulose Klucel® HPC EF 0.313.85 Hydroxypropyl cellulose Dibutyl sebacate 0.62 7.69 Talc 1.23 15.38Water 4.84 — Ethanol, 95% 87.16 —

In this coating formulation the talc content was set to 20% that of thepolymers and the water content was 10 wt % of the solvent.

The granulation was coated with the functional coating described inTable 6 using a Wurster column insert in a fluid bed. The coatingconditions are provided in FIG. 21. The spray rate was reduced to avoidover-wetting and the ambient air was humidified. The functional coatingwas applied to achieve a granulation having a 20% wg, 30% wg, and 35%wg. There was minimal agglomeration. SEM images of the granulationhaving a 35% wg functional coating are shown in FIGS. 7A-7C atmagnifications of 27×, 110×, and 1000×, respectively.

The water content of the uncoated granulation was 1.24 wt % and for thecoated granulation was 0.23 wt %.

The dissolution profile of the granulation was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 8.

Example 8 Coated Granulation (8)

A granulation containing granules having 98.5 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by agranule diameter from 200 μm to 425 μm was used.

In this coating formulation and processing conditions were similar tothat of Example 6 except that the batch size was increased from 425 g to500 g.

The constituents of the functional coating formulation are provided inTable 7.

TABLE 7 Functional coating formulation. Component Total (wt %) Solids(wt %) Aquaion® EC N10 5.85 73.08 ethylcellulose Klucel® HPC EF 0.313.85 Hydroxypropyl cellulose Dibutyl Sebacate 0.62 7.69 Talc 1.23 15.38Water 4.84 — Ethanol, 95% 87.16 —

The granulation was coated with the functional coating described inTable 7 using a Wurster column insert in a fluid bed. The coatingconditions are provided in FIG. 21. The functional coating was appliedto achieve a granulation having a 20% wg, 30% wg, and 35% wg. There wasminimal agglomeration. SEM images of the granulation having a 35% wgfunctional coating are shown in FIGS. 9A-9C at magnifications of 27×,110×, and 340×, respectively.

The water content of the undried uncoated granulation was 2.42 wt %, ofthe dried uncoated granulation was 0.21 wt %, and for the 35% wg coatedgranulation was 0.25 wt %.

The dissolution profile of the granulation was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 10.

The particle size distribution of the granulation having a 35% wgcoating is shown in FIG. 11.

Example 9 Coated Granulation (9)

A granulation containing granules having 98.5 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by agranule diameter from 200 μm to 425 μm was used.

In this example the granulation was first coated with a hydroxypropylcellulose seal coat before applying the functional coating. The sealcoat was applied to a 5% wg and the constituents of the seal coatformulation are provided in Table 8.

TABLE 8 Seal coat formulation. Component Total (wt %) Solids (wt %)Klucel® HPC EF 6.00 100 Hydroxypropyl cellulose Water 4.95 — Ethanol,95% 89.05 —

The processing condition for applying the seal coat are provided in FIG.21 (9A).

The constituents of the functional coating formulation are provided inTable 9.

TABLE 9 Functional coating formulation. Component Total (wt %) Solids(wt %) Aquaion® EC N10 5.85 73.08 ethylcellulose Klucel® HPC EF 0.313.85 Hydroxypropyl cellulose Dibutyl Sebacate 0.62 7.69 Talc 1.23 15.38Water 4.84 — Ethanol, 95% 87.16 —

The granulation was coated with the functional coating described inTable 9 using a Wurster column insert in a fluid bed. The functionalcoating application conditions are provided in FIG. 21 (9B). Thefunctional coating was applied to achieve a granulation having a 20% wg,30% wg, and 35% wg. There was minimal agglomeration. SEM images of thegranulation having a 30% wg functional coating are shown in FIGS.12A-12C at magnifications of 50×, 130×, and 500×, respectively. SEMimages of the granulation having a 35% wg functional coating are shownin FIGS. 13A-13C at magnifications of 27×, 110×, and 340×, respectively.

The dissolution profile of the granulations was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 14.

The particle size distribution of the granulations having a 35% wgcoating of Examples 7, 8, and 9 is compared in FIG. 15.

The dissolution profiles for the granulations having 20% wg, 30% wg, and35% wg functional coatings of Examples 7, 8, and 9 are compared in FIGS.16-18, respectively.

Example 10 Coated Granulation (10)

A granulation containing granules having 90.0 wt % of the compound ofFormula (2a), 4-((L-valyl)oxy)butanoic acid, and characterized by aparticle size from 225 μm to 400 μm was used. The uncoated granulationcomprising 4-((L-valyl)oxy)butanoic acid was prepared using MicroPX®micro-pelletizing technology (Glatt GmbH).

TABLE 10 Seal coat formulation. Component Total (wt %) Solids (wt %)Klucel® HPC EF 6.00 100 Hydroxypropyl cellulose Water 4.95 — Ethanol,95% 89.05 —

The constituents of the functional coating formulation are provided inTable 11.

TABLE 11 Functional coating formulation. Component Total (wt %) Solids(wt %) Aquaion® EC N10 5.84 73.00 ethylcellulose Klucel® HPC EF 0.313.88 Hydroxypropyl cellulose Dibutyl Sebacate 0.62 7.75 Talc Pharma 4001.23 15.38 Treated Water 9.20 — Ethanol, ≥95.5% 82.20 — 200 proof,anhydrous

The granulation was coated with the functional coating described inTable 11 using a Wurster column insert in a fluid bed. The functionalcoating application conditions are provided in Table 12

TABLE 12 Coating application conditions. Susp. Weight Spray In. Ex. Att.Room Time Sprayed Gain Rate Temp Temp Process Atom (psi) Dew PointParameter (min) (g) (%) (g/min) (° C.) (° C.) Air (cpm) Air (psi) Air (°C.) Target 8500 20 15 33-34 75-95 65 20-25 10-13 Range 8480-8520 10-3530-35 60-110 60-70 15-25  7-16 Coating 241 3751 20 16 40.2 32.6 85 64.220 12.4 Run SB1 Coating 340 3753 20 16 40.1 32.7 85 64.5 20 12.4 Run SB2

The functional coating was applied to achieve a coated granulationhaving a 20% wg, 25% wg, and 30% wg functional coating.

Coated granulations having a 20% wg functional coating had a bulkdensity of 0.629 g/mL. The particle size distribution as provided inTable 13.

TABLE 13 Particle Size distribution. Particle Size (μm) <210 210 300 425600 840 1190 % of Coated 0. 12.8 72.0 11.9 3.0 0.4 0 Granulation

In the coated pharmaceutical granulation 12.9% of the coated granulescan have a particle size less than 300 μm, 83.8% of the coated granulescan have a particle size from 300 μm to 600 μm, and 3.3% of the coatedgranules can have a particle size from 600 μm to 1190 μm.

The dissolution profile of the granulations was determined using a USPType 2 dissolution apparatus in a buffered solution at pH 4.5 at atemperature of 37° C. and a paddle speed of 75 rpm. The dissolutionprofiles are shown in FIG. 22.

Example 11 Water-Based Seal Coated Granulation of4-((L-Valyl)oxy)butanoic Acid

A seal-coated granulation was prepared by spray coating an uncoatedgranulation of 4-((L-valyl)oxy)butanoic acid granules.

The uncoated granulation comprising 4-((L-valyl)oxy)butanoic acid wasprepared using MicroPX® micro-pelletizing technology (Glatt GmbH). Theuncoated granulation had an average granule size (D50) from 225 μm to275 μm.

The composition used to provide the seal coat contained 14.2 wt %hydroxypropylmethyl cellulose (Pharmacoat® 603), 2.1 wt % talc and 85.6wt % water, where wt % is based on the total weight of the seal coatcomposition.

The composition was sprayed-coated onto the uncoated granulation toprovide a seal coating having a thickness of 2.23 (+/−0.34) μm.

Example 12 Acetone-Based Seal Coated Granulation of4-((L-Valyl)oxy)butanoic Acid

A seal-coated granulation was prepared by spray coating an uncoatedgranulation of 4-((L-valyl)oxy)butanoic acid granules.

The uncoated granulation comprising 4-((L-valyl)oxy)butanoic acid wasprepared using MicroPX® micro-pelletizing technology (Glatt GmbH). Theuncoated granulation had an average granule diameter (D50) from 225 μmto 275 μm.

The composition used to provide the seal coat contained 5.4 wt %hydroxypropyl cellulose (Klucel® EF), 2.1 wt % talc and 92.5 wt %acetone, where wt % is based on the total weight of the seal coatcomposition.

The composition was sprayed-coated onto the uncoated granulation toprovide a seal coating having a thickness of 1.30 (+/−0.27) μm.

It should be noted that there are alternative ways of implementing theembodiments disclosed herein. Accordingly, the present embodiments areto be considered as illustrative and not restrictive. Furthermore, theclaims are not to be limited to the details given herein and areentitled their full scope and equivalents thereof.

What is claimed is:
 1. A pharmaceutical granulation comprising aplurality of coated granules, wherein, the coated granules comprise acore and a functional coating surrounding the core; the core comprisesgreater than 85 wt % of an active pharmaceutical ingredient, wherein theactive pharmaceutical ingredient has an aqueous solubility greater than100 mg/mL; and wt % is based on the total weight of the core; and thefunctional coating comprises a plasticizer.
 2. The pharmaceuticalgranulation of claim 1, wherein the pharmaceutical granulation comprisesfrom 50 wt % to 90 wt % of the active pharmaceutical ingredient, whereinwt % is based on the total weight of the pharmaceutical granulation. 3.The pharmaceutical granulation of claim 1, wherein the functionalcoating comprises from 60 wt % to 85 wt % of a matrix polymer, whereinwt % is based on the total weight of the functional coating.
 4. Thepharmaceutical granulation of claim 3, wherein the matrix polymercomprises a water-insoluble polymer.
 5. The pharmaceutical granulationof claim 4, wherein the water-insoluble polymer comprisesethylcellulose.
 6. The pharmaceutical granulation of claim 1, whereinthe functional coating comprises from 0.5 wt % to 20 wt % of a watersoluble polymer, wherein wt % is based on the total weight of the matrixpolymer.
 7. The pharmaceutical granulation of claim 6, wherein the watersoluble polymer comprises hydroxypropyl cellulose.
 8. The pharmaceuticalgranulation of claim 6, wherein the matrix polymer comprises from 92 wt% to 98 wt % of a water-insoluble polymer and from 2 wt % to 8 wt % of awater-soluble polymer, wherein wt % is based on the total weight of thematrix polymer.
 9. The pharmaceutical granulation of claim 1, whereinthe functional coating comprises from 3 wt % to 13 wt % of theplasticizer, wherein wt % is based on the total weight of the functionalcoating.
 10. The pharmaceutical granulation of claim 9, wherein theplasticizer comprises dibutyl sebacate.
 11. The pharmaceuticalgranulation of claim 1, wherein the functional coating comprises from 10wt % to 20 wt % an antistatic agent, wherein wt % is based on the totalweight of the functional coating.
 12. The pharmaceutical granulation ofclaim 10, wherein the antistatic agent comprises talc.
 13. Thepharmaceutical granulation of claim 1, wherein the functional coatingcomprises: from 60 wt % to 85 wt % of a matrix polymer; from 10 wt % to20 wt % of an antistatic agent; and from 3 wt % to 13 wt % of theplasticizer, wherein wt % is based on the total weight of the functionalcoating.
 14. The pharmaceutical granulation of claim 1, wherein thecoated granules comprise: from 55 wt % to 90 wt % of the core; and from10 wt % to 45 wt % of the functional coating, wherein wt % is based onthe total weight of the coated granules.
 15. The pharmaceuticalgranulation of claim 1, wherein the functional coating has a thicknessfrom 5 μm to 30 μm.
 16. The pharmaceutical granulation of claim 1,wherein the active pharmaceutical ingredient has an aqueous solubilitygreater than 100 mg/mL.
 17. The pharmaceutical granulation of claim 1,wherein the active pharmaceutical ingredient comprises γ-hydroxybutyricacid or a pharmaceutically acceptable salt thereof.
 18. Thepharmaceutical granulation of claim 1, wherein the active pharmaceuticalingredient comprises a derivative of γ-hydroxybutyric acid or apharmaceutically acceptable salt thereof.
 19. The pharmaceuticalgranulation of claim 1, wherein the active pharmaceutical ingredientcomprises a compound of Formula (2):

or a pharmaceutically acceptable salt thereof, wherein, R¹ is selectedfrom hydrogen and C₁₋₆ alkyl; and each of R² and R³ is independentlyselected from hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, and C₃₋₆cycloalkoxycarbonyl.
 20. The pharmaceutical granulation of claim 1,wherein the active pharmaceutical ingredient is selected from:4-(((tert-butoxycarbonyl)glycyl)oxy)butanoic acid; 4-(glycyloxy)butanoicacid; 4-((D-valyl)oxy)butanoic acid; 4-((L-alanyl)oxy)butanoic acid;4-(((ethoxycarbonyl)glycyl)oxy)butanoic acid;4-(((isopropoxycarbonyl)glycyl)oxy)butanoic acid;4-((((cyclohexyloxy)carbonyl)glycyl)oxy)butanoic acid;4-(((ethoxycarbonyl)-D-valyl)oxy)butanoic acid; 4-((L-valyl)oxy)butanoicacid; a pharmaceutically acceptable salt of any of the foregoing; and acombination of any of the foregoing.
 21. The pharmaceutical granulationof claim 1, wherein the active pharmaceutical ingredient comprises4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable saltthereof:


22. The pharmaceutical granulation of claim 1, wherein the coatedgranules are characterized by a particle size distribution (PSD) (D50)from 150 μm to 500 μm, wherein the particle size distribution isdetermined by laser diffraction.
 23. A pharmaceutical compositioncomprising the pharmaceutical granulation of claim 1
 24. Thepharmaceutical composition of claim 23, wherein the pharmaceuticalcomposition comprises from 500 mg equivalents to 12 g equivalents ofγ-hydroxybutyric acid.
 25. The pharmaceutical composition of claim 23,wherein the active pharmaceutical ingredient comprises4-((L-valyl)oxy)butanoic acid (2a) or a pharmaceutically acceptable saltthereof:


26. The pharmaceutical composition of claim 23, wherein thepharmaceutical composition comprises a therapeutically effective amountof the active pharmaceutical ingredient for treating excessive daytimesleepiness associated with narcolepsy, excessive daytime sleepinessassociated with Parkinson's disease, excessive daytime sleepinessassociated with multiple sclerosis, cataplexy associated withnarcolepsy, fatigue in a patient with Parkinson's disease, fatigue in apatient with multiple sclerosis, or fibromyalgia.
 27. A method ofproviding a therapeutically effective amount of γ-hydroxybutyric acid inthe systemic circulation of a patent for treating a disease comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the pharmaceutical composition of claim 23 fortreating the disease. wherein the disease is selected from excessivedaytime sleepiness associated with narcolepsy, excessive daytimesleepiness associated with Parkinson's disease, excessive daytimesleepiness associated with multiple sclerosis, cataplexy associated withnarcolepsy, fatigue in a patient with Parkinson's disease, fatigue in apatient with multiple sclerosis, and fibromyalgia.